I. A. Babar, C. J. Cheng, C. J. Booth, X. Liang, J. B. Weidhaas et al., Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma, vol.109, pp.1695-704, 2012.

K. Bagrintseva, S. Geisenhof, R. Kern, S. Eichenlaub, C. Reindl et al., FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L), Blood, vol.105, issue.9, pp.3679-85, 2004.

N. Bandi, S. Zbinden, M. Gugger, M. Arnold, V. Kocher et al., miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer, Cancer Res, vol.69, issue.13, pp.5553-5562, 2009.

B. Barré, A. Vigneron, and O. Coqueret, The STAT3 transcription factor is a target for the Myc and riboblastoma proteins on the Cdc25Apromoter, J Biol Chem, vol.280, issue.16, pp.15673-81, 2005.

J. Bartek and J. Lukas, Pathways governing G1/S transition and their response to DNA damage, FEBS Lett, vol.490, issue.3, pp.117-139, 2001.

F. Basit, M. Andersson, and A. Hultquist, The Myc/Max/Mxd Network Is a Target of Mutated Flt3 Signaling in Hematopoietic Stem Cells in Flt3-ITD-Induced Myeloproliferative Disease, Stem Cells Int, p.3286949, 2018.

K. Behrens, K. Maul, N. Tekin, N. Kriebitzsch, D. Indenbirken et al., RUNX1 cooperates with FLT3-ITD to induce leukemia, J Exp Med, vol.214, issue.3, pp.737-752, 2017.

T. Ben-yosef, O. Yanuka, D. Halle, and N. Benvenisty, Involvement of Myc targets in c-myc and Nmyc induced human tumors, Oncogene, vol.17, issue.2, pp.165-71, 1998.

T. Bertero, . Gastaldi, . Bourget-ponzio, . Mari, P. Meneguzzi et al., CDC25A targeting by miR-483-3p decreases CCND-CDK4/6 assembly and contributes to cell cycle arrest, Cell Death Differ, vol.20, issue.6, pp.800-811, 2013.

. Bertoli, CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia, Oncotarget, vol.6, pp.38061-38078, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01594827

S. Bertoli and C. Récher, Nouvelles thérapies ciblées dans les leucémies aiguës myéloïdes, Journal de Biologie Médicale, vol.25, 2018.

S. Bertoli, Targeted therapies in the spotlight

N. 1. Bhowmick, M. Ghiassi, M. Aakre, K. Brown, V. Singh et al., TGF-beta-induced RhoA and p160ROCK activation is involved in the inhibition of Cdc25A with resultant cell-cycle arrest, Proc Natl Acad Sci, vol.100, issue.26, pp.15548-53, 2003.

. Birg-f-1, M. Courcoul, O. Rosnet, F. Bardin, M. J. Pébusque et al., Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages, Blood, vol.80, pp.2584-2593, 1992.

K. Biswas, S. Philip, A. Yadav, B. K. Martin, S. Burkett et al., BRE/BRCC45 regulates CDC25A stability by recruiting USP7 in response to DNA damage, Nat Commun, vol.9, p.537, 2018.

C. Böiers, N. Buza-vidas, C. T. Jensen, C. J. Pronk, S. Kharazi et al., Expression and role of FLT3 in regulation of the earliest stage of normal granulocytemonocyteprogenitor development, Blood, vol.115, issue.24, pp.5061-5069, 2010.

D. Bonci, V. Coppola, M. Musumeci, A. Addario, R. Giuffrida et al., The miR-15a-miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities, Nat Med, vol.14, issue.11, pp.1271-1278, 2008.

G. M. Borchert, W. Lanier, and B. L. Davidson, RNA polymerase III transcribes human microRNAs, Nat Struct Mol Biol, vol.13, issue.12, pp.1097-101, 2006.

P. Bose, V. Gandhi, and M. Konopleva, Pathways and mechanisms of venetoclax resistance, Leuk Lymphoma, vol.58, issue.9, pp.1-17, 2017.

A. Bottoni, D. Piccin, F. Tagliati, A. Luchin, and M. C. Zatelli, degli Uberti EC. miR-15a and miR-16-1 downregulation in pituitary adenomas, J Cell Physiol, vol.204, issue.1, pp.280-285, 2005.

R. Boutros, C. Dozier, and B. Ducommun, The when and wheres of CDC25 phosphatases, Curr Opin Cell Biol, vol.18, issue.2, pp.185-91, 2006.
URL : https://hal.archives-ouvertes.fr/hal-00317392

R. Boutros, V. Lobjois, and B. Ducommun, CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer, vol.7, pp.495-507, 2007.

K. Brasel, H. J. Mckenna, P. J. Morrissey, K. Charrier, A. E. Morris et al., Hematologic effects of flt3 ligand in vivo in mice, Blood, vol.88, issue.6, pp.2004-2016, 1996.

G. A. Cimmino-a-1-,-calin, M. Fabbri, M. V. Iorio, M. Ferracin, M. Shimizu et al., Role of DNMT3A, TET2, and IDH1/2 mutations in preleukemic stem cells in acute myeloid leukemia, Proc Natl Acad Sci, vol.102, issue.39, pp.648-57, 2005.

C. W. Chang, H. Y. Chou, Y. S. Lin, K. H. Huang, C. J. Chang et al., Phosphorylation at Ser473 regulates heterochromatin protein 1 binding and corepressor function of TIF1beta/KAP1, BMC Mol Biol, vol.9, p.61, 2008.

S. Chang, R. H. Wang, K. Akagi, K. A. Kim, B. K. Martin et al.,

D. C. Haines, M. Basik, P. Mai, E. Poggi, C. Isaacs et al., Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Nat Med, vol.17, issue.10, pp.1275-82, 2011.

K. H. Chang, F. Vincent, and K. Shah, Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death, J Cell Sci, vol.125, pp.5124-5161, 2012.

N. Chatterjee, P. Sanphui, S. Kemeny, L. A. Greene, and S. C. Biswas, Role and regulation of Cdc25A phosphatase in neuron death induced by NGF deprivation or ?-amyloid, Cell Death Discov, vol.2, p.16083, 2016.

X. Chen and R. Prywes, Serum-induced expression of the cdc25A gene by relief of E2F-mediated repression, Mol Cell Biol, vol.19, issue.7, pp.4695-702, 1999.

M. S. Chen and C. E. Ryan, Piwnica-Worms H. Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding, Mol Cell Biol, vol.23, issue.21, pp.7488-97, 2003.

X. Chen, Y. Ba, L. Ma, X. Cai, Y. Yin et al., Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases, Cell Res, vol.18, issue.10, pp.997-1006, 2008.

H. Chen, Y. W. Lin, Y. Q. Mao, J. Wu, Y. F. Liu et al., MicroRNA-449a

C. Q. Chen, C. S. Chen, J. J. Chen, L. P. Zhou, H. L. Xu et al., Histone deacetylases inhibitor trichostatin A increases the expression of Dleu2/miR-15a/16-1 via HDAC3 in non-small cell lung cancer, Mol Cell Biochem, vol.383, issue.1-2, pp.137-185, 2013.

M. T. Chen, L. Dong, X. H. Zhang, X. L. Yin, H. M. Ning et al., ZFP36L1 promotes monocyte/macrophage differentiation by repressing CDK6. Sci Rep, vol.5, p.16229, 2015.

H. H. Chen, Y. F. Lan, H. F. Li, C. F. Cheng, P. F. Lai et al., Urinary miR-16 transactivated by C/EBP? reduces kidney function after ischemia/reperfusion-induced injury. Sci Rep, vol.6, p.27945, 2016.

S. S. Chen, C. H. Tang, M. J. Chie, C. H. Tsai, Y. C. Fong et al., Wang SW Resistin facilitates VEGF-A-dependent angiogenesis by inhibiting miR-16-5p in human chondrosarcoma cells, Cell Death Dis, vol.17, issue.1, p.31, 2019.

Z. Chen, Y. Zhu, X. Fan, Y. Liu, and Q. Feng, Decreased expression of miR-184 restrains the growth and invasion of endometrial carcinoma cells through CDC25A-dependent Notch signaling pathway, Am J Transl Res, vol.11, issue.2, pp.755-764, 2019.

Y. Chen, X. Li, H. Liao, X. Leung, J. He et al., CFTR mutation compromises spermatogenesis by enhancing miR-15b maturation and suppressing its regulatory target CDC25A, Biol Reprod, 2019.

Y. Cheon and S. Lee, CENP-W inhibits CDC25A degradation by destabilizing the SCF ?-TrCP-1 complex at G 2 /M, FASEB J, 2018.

C. Choudhary, J. Schwäble, C. Brandts, L. Tickenbrock, B. Sargin et al., AML-associated FLT3 kinase domaine mutations show signal transduction differences comparedwith Flt3 ITD mutations, Blood, vol.106, issue.1, pp.265-73, 2005.

C. Choudhary, C. Brandts, J. Schwable, L. Tickenbrock, B. Sargin et al., Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood, vol.110, pp.370-374, 2007.

. Choudhary, , 2009.

C. Choudhary, J. V. Olsen, C. Brandts, J. Cox, P. N. Reddy et al., Mislocalized activation of concogenic switches downstream signaling outcomes, Mol Cell, vol.36, issue.2, pp.326-365, 2009.

R. A. Chougule, J. U. Kazi, and L. Rönnstrand, FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia, Oncotarget, vol.7, issue.9, pp.9964-74, 2016.

D. M. Cittelly, P. M. Das, V. A. Salvo, J. P. Fonseca, M. E. Burow et al., Oncogenic HER2{Delta}16 suppresses miR-15a/16 and deregulates BCL-2 to promote endocrine resistance of breast tumors, Carcinogenesis, vol.31, issue.12, pp.2049-57, 2010.

J. Cortes, S. Khaled, G. Martinelli, A. E. Perl, S. Ganguly et al., QUIZARTINIB SIGNIFICANTLY PROLONGS OVERALL SURVIVAL IN PATIENTS WITH FLT3-INTERNAL TANDEM DUPLICATION-MUTATED (MUT) RELAPSED/REFRACTORY AML IN THE PHASE 3, RANDOMIZED, CONTROLLED QUANTUM-R TRIAL, p.218882, 2018.

L. Coffer-pj-1-,-koenderman and R. P. De-groot, The role of STATs in myeloid differentiation and leukemia, Oncogene, vol.19, issue.21, pp.2511-2533, 2000.

G. M. Crane, E. Jeffery, and S. J. Morrison, Adult haematopoietic stem cell niches, Nat Rev Immunol, vol.17, issue.9, pp.573-590, 2017.

G. Cutrona, S. Matis, M. Colombo, C. Massucco, G. Baio et al., Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy, vol.31, pp.1894-1904, 2017.

F. D'alò, D. Ruscio, A. Guidi, F. Fabiani, E. Greco et al., PU.1 and CEBPA expression in acute myeloid leukemia, Leuk Res, vol.32, issue.9, pp.1448-53, 2008.

. Dahl, Regulation of macrophage and neutrophil cell fates by the PU.1 : C/EBPalpha ratio and granulocyte colony-stimulating factor, Nat Immunol, vol.4, issue.10, pp.1029-1065, 2003.

R. R. Daga and J. Jimenez, Translational control of the cdc25 cell cycle phosphatase: a molecular mechanism coupling mitosis to cell growth, J Cell Sci, vol.112, pp.3137-3183, 1999.

N. Daver, J. Cortes, F. Ravandi, K. P. Patel, J. A. Burger et al., Secondary mutations as mediators of resistance to targeted therapy in leukemia, Blood, vol.125, issue.21, pp.3236-3245, 2015.

N. Daver, R. F. Schlenk, N. H. Russel, and M. J. Levis, Targeting FLT3 mutations in AML: review of current knowledge and evidence, Leukemia, vol.33, issue.2, pp.299-312, 2019.

E. Dejean, M. H. Renalier, M. Foisseau, X. Agirre, N. Joseph et al., Hypoxia-microRNA-16 downregulation induces VEGF expression in anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphomas, Leukemia, vol.25, issue.12, pp.1882-90, 2011.
URL : https://hal.archives-ouvertes.fr/hal-00611903

A. R. Demidova, M. Y. Aau, L. Zhuang, and Q. Yu, Dual regulation of Cdc25A by Chk1 and p53-ATF3 in DNA replication checkpoint control, J Biol Chem, vol.284, issue.7, pp.4132-4141, 2009.

A. M. Denli, B. B. Tops, R. H. Plasterk, R. F. Ketting, and G. J. Hannon, Processing of primary microRNAs by the Microprocessor complex, Nature, vol.432, issue.7014, pp.231-236, 2004.

C. Desterke, C. Bilhou-nabéra, B. Guerton, C. Martinaud, C. Tonetti et al., French Intergroup of Myeloproliferative Disorders

E. European and . Networks-on-myelofibrosis, FLT3-mediated p38-MAPK activation participates in the control of megakaryopoiesis in primary myelofibrosis, Cancer Res, vol.71, issue.8, pp.2901-2916, 2011.

. Drusco-a-1 and C. M. Croce, MicroRNAs and Cancer: A Long Story for Short RNAs, Adv Cancer Res, vol.135, pp.1-24, 2017.

Y. Ebihara, K. Tsuji, S. D. Lyman, X. Sui, M. Yoshida et al., Synergistic action of Flt3 and gp130 signalings in human hematopoiesis, Blood, 1997.

F. Esposito, G. M. Pierantoni, S. Battista, R. M. Melillo, S. Scala et al., Interaction between HMGA1 and retinoblastoma protein is required for adipocyte differentiation, J Biol Chem, vol.284, issue.38, pp.25993-6004, 2009.

V. Esteban, M. D. Vázquez-novelle, E. Calvo, A. Bueno, and M. P. Sacristán, Human Cdc14A reverses CDK1 phosphorylation of Cdc25A on serines 115 and 320, Cell Cycle, vol.5, issue.24, pp.2894-2902, 2006.

M. Eytan, C. D. Stein, D. A. Dinardo, . Pollyea, T. Amir et al.,

R. M. Altman, I. W. Stone, . Flinn, M. Hagop, R. Kantarjian et al., MUTANT-IDH2 RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA, p.181758, 2017.

J. Falck, N. Mailand, R. G. Syljuåsen, J. Bartek, and J. Lukas, The ATM-Chk2-CDC25A checkpoint pathway guards against radioresistant DNA synthesis, Nature, vol.410, issue.6830, pp.842-849, 2001.

A. T. Fathi, O. Arowojolu, I. Swinnen, T. Sato, T. Rajkhowa et al., A potential therapeutic target for FLT3-ITD AML: PIM1 kinase, Leuk Res, vol.36, issue.2, pp.224-255, 2012.

X. Feng, Z. Wu, Y. Wu, W. Hankey, T. W. Prior et al., Cdc25A Regulates Matrix Metalloprotease 1 through Foxo1 and Mediates Metastasis of Breast Cancer Cells, Mol Cell Biol, vol.31, issue.16, pp.3457-3471, 2011.

Y. H. Feng and C. J. Tsao, Emerging role of microRNA-21 in cancer, vol.5, pp.395-402, 2016.

A. Fernandez-vidal, L. Ysebaert, C. Didier, R. Betous, D. Toni et al., Cell adhesion regulates CDC25A expression and proliferation in acute myeloid leukemia, Cancer Res, vol.66, issue.14, pp.7128-7163, 2006.
URL : https://hal.archives-ouvertes.fr/hal-00107359

A. Fernandez-vidal, A. Mazars, E. F. Gautier, G. Prévost, B. Payrastre et al., Upregulation of the CDC25A phosphatase down-stream of the NPM/ALK oncogene participates to anaplastic large cell lymphoma enhanced proliferation, Cell Cycle, vol.8, issue.9, pp.1373-1382, 2009.
URL : https://hal.archives-ouvertes.fr/hal-02666621

S. Ferrari and C. Gentili, Maintaining Genome Stability in Defiance of Mitotic DNA Damage. Front Genet, vol.7, p.128, 2016.

F. Jones, M. Lal, and A. , MicroRNAs, wild-type and mutant p53: More questions than answers, RNA Biol, vol.9, issue.6, pp.781-791, 2012.

I. P. Foskolou, D. Stellas, I. Rozani, M. D. Lavigne, and P. K. Politis, Prox1 suppresses the proliferation of neuroblastoma cells via a dual action in p27-Kip1 and Cdc25A, Oncogene, vol.32, issue.8, pp.947-60, 2013.

D. Frasca, MicroRNAs miR-155 and miR-16 Decrease AID and E47 in B Cells from Elderly Individuals, J Immunol, vol.195, issue.5, pp.2134-2174, 2015.

A. D. Friedman, Transcriptional regulation of myelopoiesis, Int J Hematol, vol.75, issue.5, pp.466-72, 2002.

S. Fröhling, R. F. Schlenk, J. Breitruck, A. Benner, S. Kreitmeier et al., Acute myeloid leukemia. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm, vol.100, pp.4372-80, 2002.

Y. R. Fu, X. J. Liu, X. J. Li, Z. Z. Shen, B. Yang et al., MicroRNA miR-21 attenuates human cytomegalovirus replication in neural cells by targeting Cdc25a, J Virol, vol.89, issue.2, pp.1070-82, 2015.

G. Gabriely, T. Wurdinger, S. Kesari, C. C. Esau, J. Burchard et al.,

A. M. Linsley, Krichevsky MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators, Mol Cell Biol, vol.28, issue.17, pp.5369-5380, 2008.

. Ghai-v-1 and K. Wang, Recent progress toward the use of circulating microRNAs as clinical biomarkers, Arch Toxicol, vol.90, issue.12, pp.2959-2978, 2016.

. Galaktionov-k-1, C. Jessus, and D. Beach, Raf1 interaction with Cdc25 phosphatase ties mitogenic signal transduction to cell cycle activation, Genes Dev, vol.9, issue.9, pp.1046-58, 1995.

. Galaktionov-k-1, X. Chen, and D. Beach, Cdc25 cell-cycle phosphatase as a target of c-myc, Nature, vol.382, issue.6591, pp.511-518, 1996.

R. E. Gale, C. Green, C. Allen, A. J. Mead, A. K. Burnett et al., Linch DC; Medical Research Council Adult Leukaemia Working Party. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia, Blood, vol.111, pp.2776-2784, 2008.

S. M. Gao, C. Y. Xing, C. Q. Chen, S. S. Lin, P. H. Dong et al., miR-15a and miR-16-1 inhibit the proliferation of leukemic cells by down-regulating WT1 protein level, J Exp Clin Cancer Res, vol.30, p.110, 2011.

S. M. Gao, J. Yang, C. Chen, S. Zhang, C. Y. Xing et al., miR-15a/16-1 enhances retinoic acidmediated differentiation of leukemic cells and is up-regulated by retinoic acid, Leuk Lymphoma, vol.52, issue.12, pp.2365-71, 2011.

R. Garzon, M. Garofalo, M. P. Martelli, R. Briesewitz, L. Wang et al., Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin, Proc Natl Acad Sci, vol.105, issue.10, pp.3945-50, 2008.

E. F. Gautier, M. Picard, C. Laurent, C. Marty, J. L. Villeval et al., The cell cycle regulator CDC25A is a target for JAK2V617F oncogene, Blood, vol.119, issue.5, pp.1190-1199, 2012.

D. Gerloff, . Grundler, . Wurm, C. Bräuer-hartmann, J. Katzerke et al., NF-?B/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia, Leukemia, vol.29, issue.3, pp.535-547, 2015.

B. Giessrigl, S. Krieger, M. Rosner, N. Huttary, P. Saiko et al., Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A degradation and cell-cycle attenuation in pancreatic carcinoma cells, Hum Mol Genet, vol.21, issue.21, pp.4615-4642, 2012.

D. G. Gilliland and J. D. Griffin, The roles of FLT3 in hematopoiesis and leukemia, Blood, vol.100, issue.5, pp.1532-1574, 2002.

A. Goloudina, H. Yamaguchi, D. B. Chervyakova, E. Appella, A. J. Fornace et al., Regulation of human Cdc25A stability by Serine 75 phosphorylation is not sufficient to activate a S phase checkpoint, Cell Cycle, vol.2, issue.5, pp.473-481, 2003.

A. S. Green, T. T. Maciel, M. A. Hospital, C. Yin, F. Mazed et al., Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia, Sci Adv, vol.1, issue.8, p.1500221, 2015.

D. Grimwade, R. K. Hills, A. V. Moorman, H. Walker, S. Chatters et al., National Cancer Research Institute Adult Leukaemia Working Group. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials, Blood, vol.116, issue.3, pp.354-65, 2010.

V. Groner-b-1-,-von-manstein and . Jak, Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition, Mol Cell Endocrinol, vol.451, pp.1-14, 2017.

P. Guglielmelli, L. Tozzi, C. Bogani, I. Iacobucci, V. Ponziani et al., Vannucchi AM; AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative) Investigators. Overexpression of microRNA-16-2 contributes to the abnormal erythropoiesis in polycythemia vera, Blood, vol.117, issue.25, pp.6923-6930, 2011.

, HAS / Service maladies chroniques et dispositifs d'accompagnement des malades / INCa / Département des recommandations pour les professionnels de santé / Novembre 2011 Guide ALD n° 30 « Leucémies aiguës de l'adulte, Guide ALD n°, vol.30, 2011.

J. Guo, R. A. Parise, J. E. Lan, J. Pan, S. S. Joo et al., Pharmacology and antitumor activity of a quinolinedione

, Anticancer Res, vol.27, issue.5A, pp.3067-73, 2007.

X. Guo, M. C. Connick, J. Vanderhoof, M. A. Ishak, and R. S. Hartley, MicroRNA-16 modulates HuR regulation of cyclin E1 in breast cancer cells, Int J Mol Sci, vol.16, issue.4, pp.7112-7144, 2015.

S. Guo, W. Guo, S. Li, W. Dai, N. Zhang et al., Serum miR-16: A Potential Biomarker for Predicting Melanoma Prognosis, J Invest Dermatol, vol.136, issue.5, pp.985-993, 2016.

R. Hamam, D. Hamam, K. A. Alsaleh, M. Kassem, W. Zaher et al., Circulating microRNAs in breast cancer: novel diagnostic and prognostic biomarkers, Cell Death Dis, vol.8, issue.9, p.3045, 2017.

. Hammer-s-1, K. K. To, Y. G. Yoo, M. Koshiji, and L. E. Huang, Hypoxic suppression of the cell cycle gene CDC25A in tumor cells, Cell Cycle, vol.6, issue.15, pp.1919-1945, 2007.

C. Hannum, J. Culpepper, D. Campbell, T. Mcclanahan, S. Zurawski et al., Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs, Nature, vol.368, issue.6472, pp.643-651, 1994.

S. Hao, C. Chen, and T. Cheng, Cell cycle regulation of hematopoietic stem or progenitor cells, Int J Hematol, vol.103, issue.5, pp.487-97, 2016.

. Harashima-h-1, N. Dissmeyer, and A. Schnittger, Cell cycle control across the eukaryotic kingdom, Trends Cell Biol, vol.23, issue.7, pp.345-56, 2013.

A. Hata, #. , and R. Kashima, Dysregulation of MicroRNA Biogenesis Machinery in CancerCrit Rev, Biochem Mol Biol, vol.51, issue.3, pp.121-134, 2016.

N. He, C. Li, X. Zhang, T. Sheng, C. S. Chen et al., Regulation of lung cancer cell growth and invasiveness by beta-TRCP, Mol Carcinog, vol.42, issue.1, pp.18-28, 2005.

D. A. Hess, L. Wirthlin, T. P. Craft, P. E. Herrbrich, S. A. Hohm et al., Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells, Blood, vol.107, issue.5, pp.2162-2169, 2006.

E. Heiss, K. Masson, C. Sundberg, M. Pedersen, J. Sun et al., Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosinephosphatase SHP2, Blood, vol.108, issue.5, pp.1542-50, 2006.

Y. Higuchi, H. Zeng, and M. Ogawa, CD38 expression by hematopoietic stem cells of newborn and juvenile mice, Leukemia, vol.17, issue.1, pp.171-175, 2003.

T. Hirade, M. Abe, C. Onishi, T. Taketani, S. Yamaguchi et al., Internal tandem duplication of FLT3 deregulates proliferation and differentiation and confers resistance to the FLT3 inhibitor AC220 by Up-regulating RUNX1 expression in hematopoietic cells, Int J Hematol, vol.103, issue.1, pp.95-106, 2016.

I. Hoffmann, G. Draetta, and E. Karsenti, Activation of the phosphatase activity of human cdc25A by a cdk2-cyclin E dependent phosphorylation at the G1/S transition, EMBO J, vol.13, issue.18, pp.4302-4312, 1994.

Y. Honaker, Piwnica-Worms H Casein Kinase 1 Functions as both Penultimate and Ultimate Kinase in Regulating Cdc25A Destruction, Oncogene, vol.29, issue.23, pp.3324-3334, 2010.

K. Horiuchi, H. Morioka, H. Takaishi, H. Akiyama, C. P. Blobel et al., Ectodomain shedding of FLT3 ligand is mediated by TACE, J Immunol, vol.182, issue.12, pp.7408-7414, 2009.

B. Hu, X. Wang, S. Hu, X. Ying, P. Wang et al., miR-21-mediated Radioresistance Occurs via Promoting Repair of DNA Double Strand Breaks, J Biol Chem, vol.292, issue.8, pp.3531-3540, 2017.

J. Hu, L. Zheng, X. Shen, Y. Zhang, C. Li et al., MicroRNA-125b inhibits AML cells differentiation by directly targeting Fes, vol.620, pp.1-9, 2017.

J. C. Huang, T. Babak, T. W. Corson, G. Chua, S. Khan et al., Using expression profiling data to identify human microRNA targets, Nat Methods, vol.4, issue.12, pp.1045-1054, 2007.

E. Huang, R. Liu, and Y. Chu, miRNA-15a/16: as tumor suppressors and more, Future Oncol, vol.11, issue.16, pp.2351-63, 2015.

S. Huang, X. Zou, J. N. Zhu, Y. H. Fu, Q. X. Lin et al., Attenuation of microRNA-16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy, J Cell Mol Med, vol.19, issue.3, pp.608-627, 2015.

. Humplikova-l-1, S. Kollinerova, T. Papajik, Z. Pikalova, M. Holzerova et al., Expression of miR-15a and miR-16-1 in patients with chronic lymphocytic leukemia, Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub, vol.157, issue.4, pp.284-93, 2013.

A. Iavarone and J. Massagué, E2F and histone deacetylase mediate transforming growth factor beta repression of cdc25A during keratinocyte cell cycle arrest, Mol Cell Biol, vol.19, issue.1, pp.916-938, 1999.

M. Isoda, Y. Kanemori, N. Nakajo, S. Uchida, K. Yamashita et al., The Extracellular Signalregulated Kinase-Mitogen-activated Protein Kinase Pathway Phosphorylates and Targets Cdc25A for SCF ?-TrCP -dependent Degradation for Cell Cycle Arrest, Catela Ivkovic T, vol.20, issue.8, pp.113-122, 2009.

R. Jackstadt and H. Hermeking, MicroRNAs as regulators and mediators of c-MYC function, Biochim Biophys Acta, issue.5, pp.544-53, 1849.

M. Jaime, M. J. Pujol, J. Serratosa, C. Pantoja, N. Canela et al., Bachs O The p21(Cip1) protein, a cyclin inhibitor, regulates the levels and the intracellular localization of CDC25A in mice regenerating livers, Hepatology, vol.35, issue.5, pp.1063-71, 2002.

X. Jia, H. Ouyang, B. A. Abdalla, H. Xu, Q. Nie et al., miR-16 controls myoblast proliferation and apoptosis through directly suppressing Bcl2 and FOXO1 activities, Biochim Biophys Acta Gene Regul Mech, issue.6, pp.674-684, 1860.

Q. Jiang, Y. Zhang, M. Zhao, Q. Li, R. Chen et al., miR-16 induction after CDK4 knockdown is mediated by c-Myc suppression and inhibits cell growth as well as sensitizes nasopharyngeal carcinoma cells to chemotherapy, Tumour Biol, vol.37, issue.2, pp.2425-2458, 2016.

G. Jin, H. Matsushita, S. Asai, H. Tsukamoto, R. Ono et al., FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression, Biochem Biophys Res Commun, vol.390, issue.3, pp.1001-1007, 2009.

W. Jin, F. Chen, K. Wang, Y. Song, X. Fei et al., miR-15a/miR-16 cluster inhibits invasion of prostate cancer cells by suppressing TGF-? signaling pathway, Biomed Pharmacother, vol.104, pp.637-644, 2018.

M. H. Jo, S. Shin, S. R. Jung, E. Kim, J. J. Song et al., Human Argonaute 2 Has Diverse Reaction Pathways on Target RNAs, Mol Cell, vol.59, issue.1, pp.117-141, 2015.

J. Johansson, T. Berg, E. Kurzejamska, M. F. Pang, V. Tabor et al., MiR-155-mediated loss of C/EBP? shifts the TGF-? response from growth inhibition to epithelial-mesenchymal transition, invasion and metastasis in breast cancer, Oncogene, vol.32, issue.50, pp.5614-5638, 2013.

S. M. Johnson, H. Grosshans, J. Shingara, M. Byrom, R. Jarvis et al., RAS is regulated by the let-7 microRNA family, Cell, vol.120, issue.5, pp.635-682, 2005.

. Johnson-cd-1, A. Esquela-kerscher, G. Stefani, M. Byrom, K. Kelnar et al., The let-7 microRNA represses cell proliferation pathways in human cells, Cancer Res, vol.67, issue.16, pp.7713-7735, 2007.

R. L. Juliano, The delivery of therapeutic oligonucleotides, Nucleic Acids Res, vol.44, issue.14, pp.6518-6548, 2016.

. Källström, , 2005.

H. Källström, A. Lindqvist, V. Pospisil, A. Lundgren, and C. K. Rosenthal, Cdc25A localisation and shuttling: characterisation of sequences mediating nuclear export and import, Exp Cell Res, vol.303, issue.1, pp.89-100, 2005.

T. Kang, Y. Wei, Y. Honaker, H. Yamaguchi, E. Appella et al., Piwnica-Worms H. GSK-3 beta targets Cdc25A for ubiquitin-mediated proteolysis, and GSK-3 beta inactivation correlates with Cdc25A overproduction in human cancers, Cancer Cell, vol.13, issue.1, pp.36-47, 2008.

H. Karsunky, M. Merad, A. Cozzio, I. L. Weissman, and M. G. Manz, Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo, J Exp Med, vol.198, issue.2, pp.305-318, 2003.

S. Kasar, E. Salerno, Y. Yuan, C. Underbayev, D. Vollenweider et al., Systemic in vivo lentiviral delivery of miR-15a/16 reduces malignancy in the NZB de novo mouse model of chronic lymphocytic leukemia, Genes Immun, vol.13, issue.2, pp.109-128, 2012.

M. A. Keaton, L. Szkotnicki, A. R. Marquitz, J. Harrison, T. R. Zyla et al., Nucleocytoplasmic Trafficking of G2/M Regulators in Yeast, Mol Biol Cell, vol.19, issue.9, pp.4006-4018, 2008.

L. M. Kelly, Q. Liu, J. L. Kutok, I. R. Williams, C. L. Boulton et al., FLT3 internal tandem duplication mutations associated with human acute myeloid leukemiasinduce myeloproliferative disease in a murine bone marrow transplant model, Blood, vol.99, issue.1, pp.310-318, 2002.

R. Corbett, N. Dhalla, R. Guin, A. He, C. Hirst et al., Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia, N Engl J Med, vol.368, issue.22, pp.2059-74, 2013.

L. Lezina, N. Purmessur, A. V. Antonov, T. Ivanova, E. Karpova et al., miR-16 and miR-26a target checkpoint kinases Wee1 and Chk1 in response to p53 activation by genotoxic stress, Cell Death Dis, vol.4, p.953, 2013.

C. W. Li, Y. H. Chu, and B. S. Chen, Construction and clarification of dynamic gene regulatory network of cancer cell cycle via microarray data. Cancer Inform, vol.2, pp.223-264, 2007.

L. Li, O. Piloto, H. B. Nguyen, K. Greenberg, K. Takamiya et al., Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model, Blood, vol.111, issue.7, pp.3849-58, 2008.

G. Li, K. L. Miskimen, Z. Wang, X. Y. Xie, J. Brenzovich et al., STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease, Blood, vol.115, issue.7, pp.1416-1440, 2010.

Y. Li, S. Zhao, Y. Zhen, Q. Li, L. Teng et al., A miR-21 inhibitor enhances apoptosis and reduces G(2)-M accumulation induced by ionizing radiation in human glioblastoma U251 cells, Brain Tumor Pathol, vol.28, issue.3, pp.209-223, 2011.

L. Li, E. Bailey, S. Greenblatt, D. Huso, and D. Small, Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knockin mice, Blood, vol.118, issue.18, pp.4935-4980, 2011.

L. Li, T. Osdal, Y. Ho, S. Chun, T. Mcdonald et al., SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells, Cell Stem Cell, vol.15, issue.4, pp.431-446, 2014.

Z. Li, P. Chen, R. Su, Y. Li, C. Hu et al., Overexpression and knockout of miR-126 both promote leukemogenesis, Blood, vol.126, issue.17, pp.2005-2020, 2015.

H. Li, M. Jiang, M. Cui, G. Feng, J. Dong et al., MiR-365 enhances the radiosensitivity of nonsmall cell lung cancer cells through targeting CDC25A, Biochem Biophys Res Commun, vol.512, issue.2, pp.392-398, 2019.

J. Liang, R. Cao, Y. Zhang, Y. Xia, Y. Zheng et al., PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis, Nat Commun, vol.7, p.12431, 2016.

Y. M. Lin, C. L. Chung, and Y. S. Cheng, Posttranscriptional regulation of CDC25A by BOLL is a conserved fertility mechanism essential for human spermatogenesis, J Clin Endocrinol Metab, vol.94, issue.7, pp.2650-2657, 2009.

T. C. Lin, P. L. Lin, Y. W. Cheng, T. C. Wu, M. C. Chou et al., MicroRNA-184 Deregulated by the MicroRNA-21 Promotes Tumor Malignancy and Poor Outcomes in Non-small Cell Lung Cancer via Targeting CDC25A and c-Myc, Ann Surg Oncol, vol.22, issue.3, pp.1532-1541, 2015.

T. L. Lin, S. A. Strickland, W. Fielder, R. B. Walter, J. Z. Hou et al., Phase Ib/2 study of venetoclax with low-dose cytarabine in treatment -naive patients age ? 65 with acute myelogenous leukemia, Journal of Clinical Oncology, vol.34, issue.15_suppl, pp.7007-7007, 2016.

. Lindqvist-a-1, H. Källström, K. Rosenthal, and C. , Characterisation of Cdc25B localisation and nuclear export during the cell cycle and in responseto stress, J Cell Sci, vol.117, pp.4979-90, 2004.

M. Lisovsky, S. E. Braun, Y. Ge, H. Takahira, L. Lu et al., Flt3-ligand production by human bone marrow stromal cells, Leukemia, vol.10, issue.6, pp.1012-1020, 1996.

. Liu-q-1, H. Fu, F. Sun, H. Zhang, Y. Tie et al., miR-16 family induces cell cycle arrest by regulating multiple cell cycle genes, Nucleic Acids Res, vol.36, issue.16, pp.5391-404, 2008.

L. Liu, E. F. Papa, M. S. Dooner, J. T. Machan, K. W. Johnson et al., Homing and long-term engraftment of long-and short-term renewal hematopoietic stem cells, PLoS One, vol.7, issue.2, p.31300, 2012.

J. Liu, B. Guo, Z. Chen, N. Wang, M. Iacovino et al., miR-125b promotes MLL-AF9-driven murine acute myeloid leukemia involving a VEGFA-mediated non-cell-intrinsic mechanism, vol.129, pp.1491-1502, 2017.

T. Liu, Z. Xu, D. Ou, J. Liu, and J. Zhang, The miR-15a/16 gene cluster in human cancer: A systematic review, J Cell Physiol, vol.234, issue.5, pp.5496-5506, 2019.

D. Llobet-navas, R. Rodriguez-barrueco, J. De-la-iglesia-vicente, M. Olivan, V. Castro et al., The microRNA 424/503 cluster reduces CDC25A expression during cell cycle arrest imposed by transforming growth factor ? in mammary epithelial cells, Mol Cell Biol, vol.34, issue.23, pp.4216-4247, 2014.

H. Löffler, R. G. Syljuåsen, J. Bartkova, J. Worm, J. Lukas et al., Distinct modes of deregulation of the proto-oncogenic Cdc25A phosphatase in human breastcancer cell lines, Oncogene, vol.22, issue.50, pp.8063-71, 2003.

S. Lopez, E. Voisset, J. C. Tisserand, C. Mosca, T. Prebet et al., An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia, Oncotarget, vol.7, issue.32, pp.51163-51173, 2009.

F. Lovat, M. Fassan, P. Gasparini, L. Rizzotto, L. Cascione et al., miR-15b/16-2 deletion promotes B-cell malignancies, Proc Natl Acad Sci, vol.112, issue.37, pp.11636-11677, 2015.

J. Lu, G. Getz, E. A. Miska, E. Alvarez-saavedra, J. Lamb et al.,

, MicroRNA expression profiles classify human cancers, Nature, vol.435, issue.7043, pp.834-842, 2005.

Y. Lu, F. Li, T. Xu, and J. Sun, miRNA-497 Negatively Regulates the Growth and Motility of Chondrosarcoma Cells by Targeting Cdc25A, Oncol Res, vol.23, issue.4, pp.155-63, 2016.

A. Lujambio, G. A. Calin, A. Villanueva, S. Ropero, M. Sánchez-céspedes et al., A microRNA DNA methylation signature for human cancer metastasis, Proc Natl Acad Sci, vol.105, issue.36, pp.13556-61, 2008.

S. D. Lyman, L. James, L. Johnson, K. Brasel, P. De-vries et al., Cloning of the human homologue of the murine flt3 ligand: a growth factor for earlyhematopoietic progenitor cells, Blood, vol.83, issue.10, pp.2795-801, 1994.

S. D. Lyman, E. W. Jacobsen, and F. Ligand, Stem/Progenitor Cell Factors With Overlapping Yet Distinct Activities, Blood, vol.91, pp.1101-1134, 1998.

K. Mackarehtschian, J. D. Hardin, K. A. Moore, S. Boast, S. P. Goff et al., Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoieticprogenitors, Immunity, vol.3, issue.1, pp.147-61, 1995.

N. Mailand, A. V. Podtelejnikov, A. Groth, M. Mann, J. Bartek et al., Regulation of G 2 /M events by Cdc25A through phosphorylation-dependent modulation of its stability, EMBO J, vol.21, issue.21, pp.5911-5920, 2002.

R. Majeti, C. Y. Park, and I. L. Weissman, Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood, Cell Stem Cell, vol.1, issue.6, pp.635-680, 2007.

M. Mandal, S. E. Powers, M. Maienschein-cline, E. T. Bartom, K. M. Hamel et al., Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2, Nat Immunol, vol.12, issue.12, pp.1212-1232, 2011.

A. Mao, Y. Liu, Y. Wang, Q. Zhao, X. Zhou et al., Zhang H miR-449a enhances radiosensitivity through modulating pRb/E2F1 in prostate cancer cells, Tumour Biol, vol.37, issue.4, pp.4831-4871, 2016.

G. Marcucci, K. Mrózek, M. D. Radmacher, R. Garzon, and C. D. Bloomfield, The prognostic and functional role of microRNAs in acute myeloid leukemia, Blood, vol.117, issue.4, pp.1121-1130, 2011.

R. Matsushita, N. Seki, T. Chiyomaru, S. Inoguchi, T. Ishihara et al., Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer, Br J Cancer, vol.113, issue.2, pp.282-291, 2015.

W. Matthews, C. T. Jordan, G. W. Wiegand, D. Pardoll, and I. R. Lemischka, A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations, Cell, vol.65, issue.7, pp.1143-52, 1991.

A. Mazars, A. Fernandez-vidal, O. Mondesert, C. Lorenzo, G. Prévost et al., A caspase-dependent cleavage of CDC25A generates an active fragment activating cyclin-dependent kinase 2 during apoptosis, Cell Death Differ, vol.16, issue.2, pp.208-226, 2009.
URL : https://hal.archives-ouvertes.fr/hal-02660118

L. Mazzolini, A. Broban, C. Froment, O. Burlet-schiltz, A. Besson et al., Phosphorylation of CDC25A on SER283 in late S/G2 by CDK/cyclin complexes accelerates mitotic entry, Cell Cycle, vol.15, issue.20, pp.2742-2752, 2016.

P. P. Medina, M. Nolde, and F. J. Slack, OncomiR addiction in an in vivo model of microRNA-21-induced pre-Bcell lymphoma, Nature, vol.467, issue.7311, pp.86-90, 2010.

M. Melixetian, D. K. Klein, C. S. Sørensen, and K. Helin, NEK11 regulates CDC25A degradation and the IRinduced G2/M checkpoint, Nat Cell Biol, vol.11, issue.10, pp.1247-53, 2009.

E. Melkun, M. Pilione, and R. F. Paulson, A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is associated with alteredcell-cycle status of early erythroid progenitor cells, Blood, vol.100, issue.10, pp.3804-3815, 2002.

D. Metcalf, Hematopoietic cytokines, Blood, vol.111, pp.485-491, 2008.

K. D. Meyer, Y. Saletore, P. Zumbo, O. Elemento, C. E. Mason et al., Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons, Cell, vol.149, issue.7, pp.1635-1681, 2012.

S. C. Meyer and R. L. Levine, Translational implications of somatic genomics in acute myeloid leukaemia, Lancet Oncol, vol.15, issue.9, pp.382-94, 2014.

M. Mizuki, R. Fenski, H. Halfter, I. Matsumura, R. Schmidt et al., Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways, Blood, vol.96, issue.12, pp.3907-3921, 2000.

M. Mizuki, J. Schwable, C. Steur, C. Choudhary, S. Agrawal et al., Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations, Blood, vol.101, issue.8, pp.3164-73, 2003.

M. Moarii and E. Papaemmanuil, Classification and risk assessment in AML: integrating cytogenetics and molecular profiling, Hematology Am Soc Hematol Educ Program, issue.1, pp.37-44, 2017.

. Mochizuki-t-1, C. Kitanaka, K. Noguchi, T. Muramatsu, A. Asai et al., Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway, J Biol Chem, vol.274, issue.26, pp.18659-66, 1999.

F. Montani, M. J. Marzi, F. Dezi, E. Dama, R. M. Carletti et al., miR-Test: a blood test for lung cancer early detection, J Natl Cancer Inst, vol.107, issue.6, p.63, 2015.

H. G. Moon, J. Yang, Y. Zheng, and Y. Jin, miR-15a/16 regulates macrophage phagocytosis after bacterial infection, J Immunol, vol.193, issue.9, pp.4558-67, 2014.

L. Morenos, Z. Chatterton, J. L. Ng, M. S. Halemba, M. Parkinson-bates et al., Hypermethylation and down-regulation of DLEU2 in paediatric acute myeloid leukaemia independent of embedded tumour suppressor miR-15a/16-1, Mol Cancer, vol.13, p.123, 2014.

L. Muñoz, A. Aventín, N. Villamor, J. Juncà, G. Acebedo et al., Immunophenotypic findings in acute myeloid leukemia with FLT3 internal tandem duplication, Haematologica, vol.88, issue.6, pp.637-682, 2003.

N. Narayan, L. Morenos, B. Phipson, S. N. Willis, G. Brumatti et al., Functionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukaemia, Leukemia, vol.31, issue.4, pp.808-820, 2017.

K. Natarajan, Y. Xie, M. Burcu, D. E. Linn, Y. Qiu et al., Pim-1 Kinase Phosphorylates and Stabilizes 130 kDa FLT3 and Promotes Aberrant STAT5 Signaling in Acute Myeloid Leukemia with FLT3 Internal Tandem Duplication, PLoS One, vol.8, issue.9, p.74653, 2013.

A. Navarro, T. Diaz, E. Gallardo, N. Viñolas, R. M. Marrades et al., Prognostic implications of miR-16 expression levels in resected non-small-cell lung cancer, J Surg Oncol, vol.103, issue.5, pp.411-416, 2011.

. Neelsen-kj-1, I. M. Zanini, R. Herrador, and M. Lopes, Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates, J Cell Biol, vol.200, issue.6, pp.699-708, 2013.

E. A. Nelson, S. R. Walker, M. Xiang, E. Weisberg, M. Bar-natan et al., The STAT5 Inhibitor Pimozide Displays Efficacy in Models of Acute Myelogenous Leukemia Driven by FLT3 Mutations, Genes Cancer, 2012.

D. X. Nguyen, T. F. Westbrook, and D. J. Mccance, Human Papillomavirus Type 16 E7 Maintains Elevated Levels of the cdc25A Tyrosine Phosphatase during Deregulation of Cell Cycle Arrest, J Virol, vol.76, issue.2, pp.619-632, 2002.

. Nicholls, S. Winter, R. Mottram, J. A. Miyan, and A. D. Whetton, Flt3 ligand can promote survival and macrophage development without proliferation in myeloid progenitor cells, Exp Hematol, vol.27, issue.4, pp.663-72, 1999.

. Nilsson-sk-1, M. E. Debatis, M. S. Dooner, J. A. Madri, P. J. Quesenberry et al., Immunofluorescence characterization of key extracellular matrix proteins in murine bone marrow in situ, J Histochem Cytochem, vol.46, issue.3, pp.371-378, 1998.

S. D. Nimer, D. Macgrogan, S. Jhanwar, and S. Alvarez, Chromosome 19 abnormalities are commonly seen in AML, M7. Blood, vol.100, pp.3838-3847, 2002.

. Ge-nybakken, . Canaani, . Roy, C. D. Morrissette, . Watt et al., Quizartinib elicits differential responses that correlate with karyotype and genotype of the leukemic clone, Leukemia, vol.30, issue.6, pp.1422-1425, 2016.

A. Nogami, K. Okada, S. Ishida, H. Akiyama, Y. Umezawa et al., Inhibition of the STAT5/Pim Kinase Axis Enhances Cytotoxic Effects of Proteasome Inhibitors on FLT3-ITD-Positive AML Cells by Cooperatively Inhibiting the mTORC1/4EBP1/S6K/Mcl-1 Pathway, Transl Oncol, vol.12, issue.2, pp.336-349, 2019.

J. O'brien, H. Hayder, Y. Zayed, and C. Peng, Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation, Front Endocrinol (Lausanne), vol.9, p.402, 2018.

M. Ogawa, Differentiation and proliferation of hematopoietic stem cells, Blood, vol.81, issue.11, pp.2844-53, 1993.

M. Okamoto, F. Hayakawa, Y. Miyata, K. Watamoto, N. Emi et al., Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD, Leukemia, vol.21, issue.3, pp.403-413, 2007.

P. E. De-oliveira, L. Zhang, Z. Wang, and J. S. Lazo, Hypoxia-mediated regulation of Cdc25A phosphatase by p21 and miR-21. Cell Cycle, vol.8, pp.3157-64, 2009.

S. H. Orkin and L. I. Zon, Hematopoiesis: an evolving paradigm for stem cell biology, Cell, vol.132, issue.4, pp.631-675, 2008.

. Ørom, F. C. Nielsen, and A. H. Lund, MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation, Mol Cell, vol.30, issue.4, pp.460-71, 2008.

M. Osawa, K. Hanada, H. Hamada, and H. Nakauchi, Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell, Science, vol.273, issue.5272, pp.242-247, 1996.

T. Otto and P. Sicinski, Cell cycle proteins as promising targets in cancer therapy, Nature Reviews Cancer, vol.17, pp.93-115, 2017.

C. A. Palma, A. Sheikha, D. Lim, T. K. Bryant, A. Vu et al., MicroRNA-155 as an inducer of apoptosis and cell differentiation in Acute Myeloid Leukaemia, Mol Cancer, vol.13, p.79, 2014.

E. Papaemmanuil, M. Gerstung, L. Bullinger, V. I. Gaidzik, P. Paschka et al., Genomic Classification and Prognosis in Acute Myeloid Leukemia, N Engl J Med, vol.374, issue.23, pp.2209-2221, 2009.

T. S. Pardee, J. Zuber, and S. W. Lowe, Flt3-ITD alters chemotherapy response in vitro and in vivo in a p53-dependent manner, Exp Hematol, vol.39, issue.4, pp.473-485, 2011.

. Paskind-m-1, C. Johnston, P. M. Epstein, J. Timm, D. Wickramasinghe et al., Structure and promoter activity of the mouse CDC25A gene, Mamm Genome, vol.11, issue.12, pp.1063-1072, 2000.

J. P. Patel, M. Gönen, M. E. Figueroa, H. Fernandez, Z. Sun et al.,

, Prognostic relevance of integrated genetic profiling in acute myeloid leukemia, N Engl J Med, vol.366, issue.12, pp.1079-89, 2012.

N. Patel, K. R. Garikapati, M. J. Ramaiah, K. K. Polavarapu, U. Bhadra et al., miR-15a/miR-16 induces mitochondrial dependent apoptosis in breast cancer cells by suppressing oncogene BMI1, Life Sci, vol.164, pp.60-70, 2016.

P. Friedman and A. , EBP? dysregulation in AML and ALL, Crit Rev Oncog, vol.16, issue.1-2, pp.93-102, 2011.

Y. Pekarsky, V. Balatti, and C. M. Croce, BCL2 and miR-15/16: from gene discovery to treatment, Cell Death Differ, vol.25, issue.1, pp.21-26, 2018.

Y. Pereg, B. Y. Liu, K. M. O'rourke, M. Sagolla, A. Dey et al., Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A, Nat Cell Biol, vol.12, issue.4, pp.400-406, 2010.

F. Pichiorri, S. S. Suh, A. Rocci, L. De-luca, C. Taccioli et al., Downregulation of p53-inducible microRNAs 192, 194, and 215 impairs the p53/MDM2 autoregulatory loop in multiple myeloma development, Cancer Cell, vol.18, issue.4, pp.367-81, 2010.

T. Placke, K. Faber, A. Nonami, S. L. Putwain, H. R. Salih et al., Requirement for CDK6 in MLL-rearranged acute myeloid leukemia, Blood, vol.124, issue.1, pp.13-23, 2014.

C. Porcher, H. Chagraoui, M. S. Kristiansen, and . Scl/tal1, , vol.129, pp.2051-2060, 2017.

E. R. Porrello, B. A. Johnson, A. B. Aurora, E. Simpson, Y. J. Nam et al., MiR-15 family regulates postnatal mitotic arrest of cardiomyocytes, Circ Res, vol.109, issue.6, pp.670-679, 2011.

J. Pothof, N. S. Verkaik, W. Van-ijcken, E. A. Wiemer, V. T. Ta et al., MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response, EMBO J, vol.28, issue.14, pp.2090-2099, 2009.

L. M. Pouliot, Y. C. Chen, J. Bai, R. Guha, S. E. Martin et al., Cisplatin sensitivity mediated by WEE1 and CHK1 is mediated by miR-155 and the miR-15 family, Cancer Res, vol.72, issue.22, pp.5945-55, 2012.

G. Pozo-molina, A. Ponciano-gómez, G. C. Rivera-gonzález, A. Hernández-zavala, and E. Garrido, Arsenicinduced S phase cell cycle lengthening is associated with ROS generation, p53 signaling and CDC25A expression, Chem Biol Interact, vol.238, pp.170-179, 2015.

M. Pratcorona, S. Brunet, J. Nomdedéu, J. M. Ribera, M. Tormo et al.,

, Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas Mieloblásticas. Favorable outcome of patients with acute myeloid leukemia harboring a lowallelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy, Blood, vol.121, pp.2734-2738, 2013.

J. Qian, J. Lin, W. Qian, J. C. Ma, S. X. Qian et al., Overexpression of miR-378 is frequent and may affect treatment outcomes in patients with acute myeloid leukemia, Leuk Res, vol.37, issue.7, pp.765-773, 2013.

H. Qin and W. Liu, MicroRNA-99a-5p suppresses breast cancer progression and cell-cycle pathway through downregulating CDC25A, J Cell Physiol, vol.234, issue.4, pp.3526-3537, 2019.

. Qiu-w-1 and M. Kassem, miR-141-3p inhibits human stromal (mesenchymal) stem cell proliferation and differentiation, Biochim Biophys Acta, vol.1843, issue.9, pp.2114-2135, 2014.

H. S. Radomska, D. S. Bassères, R. Zheng, P. Zhang, T. Dayaram et al., Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations, J Exp Med, vol.203, issue.2, pp.371-81, 2006.

H. S. Radomska, A. , M. , W. B. Gonzalez, D. Delwel et al., Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBP?, J Clin Invest, vol.122, issue.8, pp.2955-66, 2012.

S. M. Raghuveer, E. A. Lasater, K. Doyle, R. Malla, E. Boghaert et al., FLT3-ITD Activation Mediates Resistance to the BCL-2 Selective Antagonist, Venetoclax, FLT3-ITD Mutant AML Models, vol.130, p.1348, 2017.

H. E. Ramsey, M. A. Fischer, T. Lee, A. E. Gorska, M. P. Arrate et al., A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia, Cancer Discov, vol.8, issue.12, pp.1566-1581, 2018.

R. J. Ray, C. J. Paige, C. Furlonger, and S. D. Lyman, Rottapel R ; Flt3 ligand supports the differentiation of early B cell progenitors in the presence of interleukin-11 and interleukin-7, Eur J Immunol, vol.26, issue.7, pp.1504-1514, 1996.

D. Ray, Y. Terao, P. G. Fuhrken, Z. Q. Ma, F. J. Demayo et al.,

, Deregulated CDC25A expression promotes mammary tumorigenesis with genomic instability, Cancer Res, vol.67, issue.3, pp.984-91, 2007.

D. Ray, Y. Terao, D. Nimbalkar, H. Hirai, E. C. Osmundson et al., Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice

C. Ren, H. Chen, C. Han, D. Fu, D. Wang et al., High expression of miR-16 and miR-451 predicating better prognosis in patients with gastric cancer, J Cancer Res Clin Oncol, vol.142, issue.12, pp.2489-2496, 2016.

W. Rizwani, C. Schaal, S. Kunigal, D. Coppola, and S. Chellappan, Mammalian lysine histone demethylase KDM2A regulates E2F1-mediated gene transcription in breast cancer cells, PLoS One, vol.9, issue.7, p.100888, 2014.

L. Robb, Cytokine receptors and hematopoietic differentiation, Oncogene, vol.26, issue.47, pp.6715-6738, 2007.

A. Rodriguez, S. Griffiths-jones, J. L. Ashurst, and A. Bradley, Identification of Mammalian microRNA Host Genes and Transcription Units, Genome Res, vol.14, issue.10a, pp.1902-1910, 2004.

O. Rosnet, H. J. Bühring, S. Marchetto, I. Rappold, C. Lavagna et al., Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells, Leukemia, vol.10, issue.2, pp.238-286, 1996.

K. Rother, R. Kirschner, K. Sänger, L. Böhlig, J. Mössner et al., p53 downregulates expression of the G1/S cell cycle phosphatase Cdc25A. Oncogene, vol.26, pp.1949-53, 2006.

J. Rudolph, Catalytic mechanism of Cdc25, Biochemistry, vol.41, issue.49, pp.14613-14636, 2002.

R. Lee, W. Chen, C. C. Liu, S. Safe, and S. , 17beta-estradiol (E2) induces cdc25A gene expression in breast cancer cells by genomic and non-genomic pathways, J Cell Biochem, vol.99, issue.1, pp.209-229, 2006.

Y. Saito, G. Liang, G. Egger, J. M. Friedman, J. C. Chuang et al., Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatinmodifying drugs in human cancer cells, Cancer Cell, vol.9, issue.6, pp.435-478, 2006.

M. Salmanidis, K. Pillman, G. Goodall, and C. Bracken, Direct transcriptional regulation by nuclear microRNAs, Int J Biochem Cell Biol, vol.54, pp.304-315, 2014.

. Sampath-d-1, C. Liu, K. Vasan, M. Sulda, V. K. Puduvalli et al., Histone deacetylases mediate the silencing of miR-15a, miR-16, and miR-29b in chronic lymphocytic leukemia, Blood, vol.119, issue.5, pp.1162-72, 2012.

V. B. Sampson, N. H. Rong, J. Han, Q. Yang, V. Aris et al., Krueger LJ MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells, Cancer Res, vol.67, issue.20, pp.9762-70, 2007.

S. Sarkar, B. K. Dey, and A. Dutta, MiR-322/424 and -503 are induced during muscle differentiation and promote cell cycle quiescence and differentiation by down-regulation of Cdc25A, Mol Biol Cell, vol.21, issue.13, pp.2138-2187, 2010.

T. Sato, X. Yang, S. Knapper, P. White, B. D. Smith et al., FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo, Blood, vol.117, issue.12, pp.3286-93, 2011.

C. M. Sawai, S. Babovic, S. Upadhaya, D. Knapp, Y. Lavin et al., Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals, Immunity, vol.45, issue.3, pp.597-609, 2016.

B. Scheijen, H. T. Ngo, H. Kang, and J. D. Griffin, FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins, Oncogene, vol.23, pp.3338-3387, 2004.

. Schlenk, , 2014.

R. F. Schlenk, S. Kayser, L. Bullinger, G. Kobbe, J. Casper et al., Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation, Blood, vol.124, pp.3441-3449, 2014.

. Schmidt-arras-de-1, A. Böhmer, B. Markova, C. Choudhary, H. Serve et al., Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases, Mol Cell Biol, vol.25, issue.9, pp.3690-703, 2005.

T. D. Schmittgen, E. J. Lee, J. Jiang, A. Sarkar, L. Yang et al., Real-time PCR quantification of precursor and mature microRNA, Methods, vol.44, issue.1, pp.31-39, 2008.

E. Schneider, A. Staffas, L. Röhner, K. Krowiorz, M. Heuser et al., MicroRNA-155 is upregulated in MLL-rearranged AML but its absence does not affect leukemiadevelopment, Exp Hematol, vol.44, issue.12, pp.1166-1171, 2016.

J. Seita and I. L. Weissman, Hematopoietic stem cell: self-renewal versus differentiation, Wiley Interdiscip Rev Syst Biol Med, vol.2, issue.6, pp.640-53, 2010.

A. Sexauer, A. Perl, X. Yang, M. Borowitz, C. Gocke et al., Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML, Blood, vol.120, issue.20, pp.4205-4219, 2012.

L. Shi, J. Zhang, T. Pan, J. Zhou, W. Gong et al., MiR-125b is critical for the suppression of human U251 glioma stem cell proliferation, Brain Res, vol.1312, pp.120-126, 2010.

L. Y. Shih, C. F. Huang, J. H. Wu, T. L. Lin, P. Dunn et al., Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse, Blood, vol.100, issue.7, pp.2387-92, 2002.

L. I. Shlush, S. Zandi, A. Mitchell, W. C. Chen, J. M. Brandwein et al., Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia, Nature, vol.506, issue.7488, pp.328-361, 2014.

N. J. Short, H. Kantarjian, F. Ravandi, and N. Daver, Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia, Ther Adv Hematol, vol.10, p.2040620719827310, 2019.

M. R. Shurin, C. Esche, and M. T. Lotze, FLT3: receptor and ligand. Biology and potential clinical application, Cytokine Growth Factor Rev, vol.9, issue.1, pp.37-48, 1998.

L. Singh, N. Pushker, S. Sen, M. K. Singh, S. Bakhshi et al., Expression of CDC25A and CDC25B phosphatase proteins in human retinoblastoma and its correlation with clinicopathological parameters, Br J Ophthalmol, vol.99, issue.4, pp.457-63, 2015.

J. I. Sive and B. Göttgens, Transcriptional network control of normal and leukaemic haematopoiesis, Exp Cell Res, vol.329, issue.2, pp.255-64, 2014.

A. Y. So, R. Sookram, A. A. Chaudhuri, A. Minisandram, D. Cheng et al., Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias, Blood, vol.124, issue.9, pp.1502-1514, 2014.

B. Song, Y. Chen, Y. Liu, C. Wan, L. Zhang et al., NPAS2 regulates proliferation of acute myeloid leukemia cells via CDC25A-mediated cell cycleprogression and apoptosis, J Cell Biochem, 2009.

R. G. Sørensen-cs-1-,-syljuåsen, J. Falck, T. Schroeder, L. Rönnstrand, K. K. Khanna et al., Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizingradiationinduced accelerated proteolysis of Cdc25A, Cancer Cell, vol.3, issue.3, pp.247-58, 2003.

D. Staudt, H. C. Murray, T. Mclachlan, F. Alvaro, A. K. Enjeti et al., Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance, Int J Mol Sci, vol.19, issue.10, p.3198, 2018.

R. A. Steinman, Cell cycle regulators and hematopoiesis, Oncogene, vol.21, issue.21, pp.3403-3416, 2002.

D. L. Stirewalt and J. P. Radich, The role of FLT3 in haematopoietic malignancies, Nat Rev Cancer, vol.3, issue.9, pp.650-65, 2003.

D. L. Stirewalt, K. J. Kopecky, S. Meshinchi, J. H. Engel, E. L. Pogosova-agadjanyan et al., Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia, Blood, vol.107, pp.3724-3726, 2006.

C. Sullivan, Y. Liu, J. Shen, A. Curtis, C. Newman et al., Novel interactions between FOXM1 and CDC25A regulate the cell cycle, PLoS One, vol.7, issue.12, p.51277, 2012.

R. P. Sullivan, J. W. Leong, S. E. Schneider, A. R. Ireland, M. M. Berrien-elliott et al., MicroRNA-15/16 Antagonizes Myb To Control NK Cell Maturation, J Immunol, vol.195, issue.6, pp.2806-2823, 2015.

C. 1. Sun, X. M. She, Y. Qin, Z. B. Chu, L. Chen et al., miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF, Carcinogenesis, vol.34, issue.2, pp.426-461, 2013.

J. Sun, A. Ramos, B. Chapman, J. B. Johnnidis, L. Le et al., Clonal dynamics of native haematopoiesis, Nature, vol.514, issue.7522, pp.322-329, 2014.

Y. P. Sun, F. Lu, X. Y. Han, J. M. Zhou, Y. Zhang et al., MiR-424 and miR-27a increase TRAIL sensitivity of acute myeloid leukemia by targeting PLAG1, Oncotarget, vol.7, issue.18, pp.25276-25290, 2016.

A. A. Svoronos, D. M. Engelman, and F. J. Slack, OncomiR or Tumor Suppressor? The Duplicity of MicroRNAs in Cancer, Cancer Res, vol.76, issue.13, pp.3666-3670, 2016.

R. Swords, C. Freeman, and F. Giles, Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia, Leukemia, vol.26, issue.10, pp.2176-85, 2012.

D. C. Taussig, F. Miraki-moud, F. Anjos-afonso, D. J. Pearce, K. Allen et al., Anti-CD38 antibodymediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells, Blood, vol.112, issue.3, pp.568-75, 2008.

B. I. Terman, M. Dougher-vermazen, M. E. Carrion, D. Dimitrov, D. C. Armellino et al., Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growthfactor, Biochem Biophys Res Commun, vol.187, issue.3, pp.1579-86, 1992.

P. Tsapogas, L. K. Swee, A. Nusser, N. Nuber, M. Kreuzaler et al., In vivo evidence for an instructive role of fms-like tyrosine kinase-3 (FLT3) ligand in hematopoietic development, Haematologica, vol.99, issue.4, pp.638-646, 2014.

P. Tsapogas, C. J. Mooney, and G. Brown, Rolink A The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis, Int J Mol Sci, vol.18, issue.6, p.1115, 2017.

S. Takahashi, Inhibition of the MEK/MAPK signal transduction pathway strongly impairs the growth of Flt3-ITD cells, Am J Hematol, vol.81, issue.2, pp.154-159, 2006.

. Takamizawa-j-1, H. Konishi, K. Yanagisawa, S. Tomida, H. Osada et al., Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival, Cancer Res, vol.64, issue.11, pp.3753-3759, 2004.

. Thiede-c-1, C. Steudel, B. Mohr, M. Schaich, U. Schäkel et al., Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis, Blood, vol.99, pp.4326-4335, 2002.

R. Tian, J. Wang, H. Yan, J. Wu, Q. Xu et al., Differential expression of miR16 in glioblastoma and glioblastoma stem cells: their correlation with proliferation, differentiation, metastasis and prognosis, vol.36, pp.5861-5873, 2017.

P. Turowski, C. Franckhauser, M. C. Morris, P. Vaglio, A. Fernandez et al., Functional cdc25C dualspecificity phosphatase is required for S-phase entry in human cells, Mol Biol Cell, vol.14, issue.7, pp.2984-98, 2003.
URL : https://hal.archives-ouvertes.fr/hal-02441367

I. Z. Uras, G. J. Walter, R. Scheicher, F. Bellutti, M. Prchal-murphy et al., Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinasedependent transcriptional regulation of FLT3 and PIM1 by CDK6, Blood, vol.127, issue.23, pp.2890-902, 2009.

C. A. Vaiana, T. Kurcon, and L. K. Mahal, MicroRNA-424 Predicts a Role for ?-1,4 Branched Glycosylation in Cell Cycle Progression, J Biol Chem, vol.291, issue.3, pp.1529-1566, 2016.

K. Van-roosbroeck, F. Fanini, T. Setoyama, C. Ivan, C. Rodriguez-aguayo et al., Calin GA Combining Anti-Mir-155 with Chemotherapy for the Treatment of Lung Cancers, Clin Cancer Res, vol.23, issue.11, pp.2891-2904, 2017.

. Vázquez-novelle-md-1, N. Mailand, S. Ovejero, A. Bueno, and M. P. Sacristán, Human Cdc14A phosphatase modulates the G2/M transition through Cdc25A and Cdc25B, J Biol Chem, vol.285, issue.52, pp.40544-53, 2010.

S. Vijayakumar, G. Liu, I. A. Rus, S. Yao, Y. Chen et al., High-frequency canonical Wnt activation in multiple sarcoma subtypes drives proliferation through a TCF/?-catenin target gene, CDC25A. Cancer Cell, vol.19, pp.601-613, 2011.

C. Vicente, A. Conchillo, M. A. García-sánchez, and M. D. Odero, The role of the GATA2 transcription factor in normal and malignant hematopoiesis, Crit Rev Oncol Hematol, vol.82, issue.1, pp.1-17, 2012.

A. Vigneron, J. Cherier, B. Barré, E. Gamelin, and O. Coqueret, The cell cycle inhibitor p21waf1 binds to the myc and cdc25A promoters upon DNA damage and induces transcriptional repression, J Biol Chem, vol.281, issue.46, pp.34742-50, 2006.

E. Vigo, H. Müller, E. Prosperini, G. Hateboer, P. Cartwright et al., CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase, Mol Cell Biol, vol.19, issue.9, pp.6379-95, 1999.

J. A. Wallace, D. A. Kagele, A. M. Eiring, C. N. Kim, R. Hu et al., promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response, vol.129, pp.3074-3086, 2017.

J. A. Wallace, O. Connell, and R. M. , MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts, vol.130, pp.1290-1301, 2017.

P. Wang, C. F. Zhu, M. Z. Ma, G. Chen, M. Song et al., Micro-RNA-155 is induced by K-Ras oncogenic signal and promotes ROS stress in pancreatic cancer, Oncotarget, vol.6, issue.25, pp.21148-58, 2015.

D. W. Wang, Y. Q. Wang, and H. S. Shu, MiR-16 inhibits pituitary adenoma cell proliferation via the suppression of ERK/MAPK signal pathway, Eur Rev Med Pharmacol Sci, vol.22, issue.5, pp.1241-1248, 2018.

S. Wegener, W. Hampe, D. Herrmann, and H. C. Schaller, Alternative splicing in the regulatory region of the human phosphatases CDC25A and CDC25C, Eur J Cell Biol, vol.79, issue.11, pp.810-815, 2000.

M. Williams, Y. Y. Cheng, C. Blenkiron, and G. Reid, Exploring Mechanisms of MicroRNA Downregulation in Cancer, Microrna, vol.6, issue.1, pp.2-16, 2017.

L. Wu, E. C. Goodwin, L. K. Naeger, E. Vigo, K. Galaktionov et al., E2F-Rb complexes assemble and inhibit cdc25A transcription in cervical carcinoma cellsfollowing repression of human papillomavirus oncogene expression, Mol Cell Biol, vol.20, issue.19, pp.7059-67, 2000.

C. F. Wu, S. Liu, Y. C. Lee, R. Wang, S. Sun et al., RSK promotes G2/M transition through activating phosphorylation of Cdc25A and Cdc25B, Oncogene, vol.33, issue.18, pp.2385-94, 2014.

M. Wu, L. Li, M. Hamaker, D. Small, and A. S. Duffield, FLT3/ITD cooperates with Rac1 to modulate the sensitivity of leukemic cells to chemotherapeuticagents via regulation of DNA repair pathways, Haematologica, 2018.

L. Xia, D. Zhang, R. Du, Y. Pan, L. Zhao et al., miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells, Int J Cancer, vol.123, issue.2, pp.372-379, 2008.

G. Xiao, H. Tang, W. Wei, J. Li, J. L. Ge et al., Aberrant Expression of MicroRNA-15a and MicroRNA, p.16

, Synergistically Associates with Tumor Progression and Prognosis in Patients with Colorectal Cancer, Gastroenterol Res Pract, p.364549, 2014.

X. Xu, H. Yamamoto, M. Sakon, M. Yasui, C. Y. Ngan et al., Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas, Clin Cancer Res, vol.9, issue.5, pp.1764-72, 2003.

X. Xu, H. Yamamoto, G. Liu, Y. Ito, C. Y. Ngan et al., CDC25A inhibition suppresses the growth and invasion of human hepatocellular carcinoma cells, Int J Mol Med, vol.21, issue.2, pp.145-52, 2008.

L. H. Xu, Y. Guo, J. N. Cen, W. Y. Yan, H. L. He et al., Overexpressed miR-155 is associated with initial presentation and poor outcome in Chinese pediatric acute myeloid leukemia, Eur Rev Med Pharmacol Sci, vol.19, issue.24, pp.4841-50, 2015.

G. Xue, H. L. Yan, Y. Zhang, L. Q. Hao, X. T. Zhu et al., c-Myc-mediated repression of miR-15-16 in hypoxia is induced by increased HIF-2? and promotes tumor angiogenesis and metastasis by upregulating FGF2, Oncogene, vol.34, issue.11, pp.1393-406, 2015.

T. Yamaura, T. Nakatani, K. Uda, H. Ogura, W. Shin et al., A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy against AML cells with FLT3 mutations, Blood, vol.131, issue.4, pp.426-438, 2018.

X. Yang, L. Liu, D. Sternberg, L. Tang, I. Galinsky et al., The FLT3 internal tandem duplication mutation prevents apoptosis in interleukin-3-deprived BaF3 cells due to protein kinase A and ribosomal S6 kinase 1-mediated BAD phosphorylation at serine112. Cancer Res, vol.65, pp.7338-7385, 2005.

X. Yang, M. Feng, X. Jiang, Z. Wu, Z. Li et al., miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A, Genes Dev, vol.23, issue.20, pp.2388-93, 2009.

X. Yang, A. Sexauer, and M. Levis, Bone marrow stroma-mediated resistance to FLT3 inhibitors in FLT3-ITD AML is mediated by persistent activation of extracellular regulated kinase, Br J Haematol, vol.164, issue.1, pp.61-72, 2014.

T. Q. Yang, X. J. Lu, T. F. Wu, D. D. Ding, Z. H. Zhao et al., MicroRNA-16 inhibits glioma cell growth and invasion through suppression of BCL2 and the nuclear factor-?B1/MMP9 signaling pathway, Cancer Sci, vol.105, issue.3, pp.265-71, 2014.

Y. Yang and Q. Mei, miRNA signature identification of retinoblastoma andthe correlations between differentially expressed miRNAs during retinoblastoma progression. Mol Vis, vol.21, pp.1307-1324, 2015.

I. P. Yang, H. L. Tsai, C. W. Huang, C. Y. Lu, Z. F. Miao et al., High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2, Oncotarget, vol.7, issue.14, pp.18837-50, 2016.

W. Ye, J. Xue, Q. Zhang, F. Li, W. Zhang et al., MiR-449a functions as a tumor suppressor in endometrial cancer by targeting CDC25A, Oncol Rep, vol.32, issue.3, pp.1193-1202, 2014.

C. H. Yi, T. Zheng, D. Leaderer, A. Hoffman, and Y. Zhu, Cancer-related transcriptional targets of the circadian gene NPAS2 identified by genome-wide ChIP-on-chip analysis, Cancer Lett, vol.284, issue.2, pp.149-56, 2009.

G. Yoshimoto, T. Miyamoto, S. Jabbarzadeh-tabrizi, T. Iino, J. L. Rocnik et al., FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation, Blood, vol.114, pp.5034-5043, 2009.

J. Yu, F. Wang, G. H. Yang, F. L. Wang, Y. N. Ma et al., Human microRNA clusters: genomic organization and expression profile in leukemia cell lines, Biochem Biophys Res Commun, vol.349, issue.1, pp.59-68, 2006.

D. D. Yu, M. M. Lv, W. X. Chen, S. L. Zhong, X. H. Zhang et al., Role of miR-155 in drug resistance of breast cancer, Tumour Biol, vol.36, issue.3, pp.1395-401, 2015.

M. Yu, Y. Xue, J. Zheng, X. Liu, H. Yu et al., Linc00152 promotes malignant progression of glioma stem cells by regulating miR-103a-3p/FEZF1/CDC25A pathway. Mol Cancer, vol.16, p.110, 2017.

L. L. Yuan, A. S. Green, S. Bertoli, F. Grimal, V. Mansat-de-mas et al., Pim kinases phosphorylate Chk1 and regulate its functions in acute myeloid leukemia, Leukemia, vol.28, issue.2, pp.293-301, 2014.

J. M. Yuan, X. J. Shi, P. Sun, J. X. Liu, W. Wang et al., Downregulation of cell cycle-related proteins in ovarian cancer line and cell cycle arrest induced by microRNA, Int J Clin Exp Med, vol.8, issue.10, pp.18476-81, 2015.

P. Yuan, J. Li, F. Zhou, Q. Huang, J. Zhang et al., NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A. Cell Death Dis, vol.8, p.2704, 2017.

J. Yue and G. Tigyi, Conservation of miR-15a/16-1 and miR-15b/16-2 clusters, Mamm Genome, vol.21, issue.1-2, pp.88-94, 2010.

S. K. Zaidi, C. R. Dowdy, A. J. Van-wijnen, J. B. Lian, A. Raza et al., Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network, Cancer Res, vol.69, issue.21, pp.8249-55, 2009.

F. C. Zeigler, B. D. Bennett, C. T. Jordan, S. D. Spencer, S. Baumhueter et al., Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells, Blood, vol.84, issue.8, pp.2422-2452, 1994.

S. Zhang and H. E. Broxmeyer, p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligandstimulated hematopoietic cells, Biochem Biophys Res Commun, vol.254, issue.2, pp.440-445, 1999.

S. Zhang, S. Fukuda, Y. Lee, G. Hangoc, S. Cooper et al., Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling, J Exp Med, vol.192, issue.5, pp.719-747, 2000.

S. Zhang and H. E. Broxmeyer, Flt3 ligand induces tyrosine phosphorylation of gab1 and gab2 and their association with shp-2, grb2, and PI3 kinase, Biochem Biophys Res Commun, vol.277, issue.1, p.195, 2000.

B. Zhang, X. Pan, G. P. Cobb, and T. A. Anderson, microRNAs as oncogenes and tumor suppressors, Dev Biol, vol.302, issue.1, pp.1-12, 2007.

X. Zhang, I. Neganova, S. Przyborski, C. Yang, M. Cooke et al., A role for NANOG in G1 to S transition in human embryonic stem cells through direct binding of CDK6 and CDC25A, J Cell Biol, vol.184, issue.1, pp.67-82, 2009.

Y. Zhang, M. Parsanejad, E. Huang, D. Qu, H. Aleyasin et al., Pim-1 kinase as activator of the cell cycle pathway in neuronal death induced by DNA damage, J Neurochem, vol.112, issue.2, pp.497-510, 2010.

T. J. Zhang, D. H. Wu, J. D. Zhou, X. X. Li, W. Zhang et al., Overexpression of miR-216b: Prognostic and predictive value in acute myeloid leukemia, J Cell Physiol, vol.233, issue.4, pp.3274-3281, 2018.

W. Zhang, Q. Zeng, Z. Ban, J. Cao, T. Chu et al., Effects of let-7c on the proliferation of ovarian carcinoma cells by targeted regulation of CDC25a gene expression, Oncol Lett, vol.16, issue.5, pp.5543-5550, 2018.

H. Zhao, J. L. Watkins, and H. Piwnica-worms, Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizingradiation-induced S and G2 checkpoints, Proc Natl Acad Sci, vol.99, issue.23, pp.14795-800, 2002.

Z. Zhao, X. Ma, D. Sung, M. Li, A. Kosti et al., microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest, RNA Biol, vol.12, issue.5, pp.538-54, 2015.

S. Zhao, Y. Wang, T. Guo, W. Yu, J. Li et al., YBX1 regulates tumor growth via CDC25a pathway in human lung adenocarcinoma, Oncotarget, vol.7, issue.50, pp.82139-82157, 2016.

Y. Zhao, F. Wang, S. Chen, J. Wan, and G. Wang, Methods of MicroRNA Promoter Prediction and Transcription Factor Mediated Regulatory Network, Biomed Res Int, p.7049406, 2017.

R. Zheng, M. Levis, O. Piloto, P. Brown, B. R. Baldwin et al., FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells, vol.103, pp.267-74, 2004.

B. Zhou, B. Shu, . Su-n-3, and J. Liu, Dub3 expression correlates with tumor progression and poor prognosis in human epithelial ovarian cancer, Biomed Pharmacother, vol.70, pp.84-93, 2015.

. Zhu-s-1, H. Wu, F. Wu, D. Nie, S. Sheng et al., MicroRNA-21 targets tumor suppressor genes in invasion and metastasis, Cell Res, vol.18, issue.3, pp.350-359, 2008.

X. Zhu, L. Wu, J. Yao, H. Jiang, Q. Wang et al., MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma, PLoS One, vol.10, issue.4, p.124266, 2015.

J. Zhu and S. G. Emerson, Hematopoietic cytokines, transcription factors and lineage commitment, Oncogene, vol.21, pp.3295-3313, 2002.

H. E. Zidan, R. S. Abdul-maksoud, W. Elsayed, and E. Desoky, Diagnostic and prognostic value of serum miR-15a and miR-16-1 expression among egyptian patients with prostate cancer. : IUBMB Life, vol.70, pp.437-444, 2018.

X. Zou, T. Tsutsui, D. Ray, J. F. Blomquist, H. Ichijo et al., The cell cycleregulatory CDC25A phosphatase inhibits apoptosis signal-regulating kinase 1, Mol Cell Biol, vol.21, issue.14, pp.4818-4846, 2001.

A. Zriwil, C. Böiers, T. A. Kristiansen, L. Wittmann, J. Yuan et al., Direct role of FLT3 in regulation of early lymphoid progenitors, Br J Haematol, vol.183, issue.4, pp.588-600, 2018.

M. I. Zubillaga-guerrero, A. Ldel, C. Illades-aguiar, B. Flores-alfaro, E. Bermúdez-morales et al., MicroRNA miR-16-1 regulates CCNE1 (cyclin E1) gene expression in human cervical cancer cells, Int J Clin Exp Med, vol.8, issue.9, pp.15999-6006, 2015.

, Véronique Mansat-De Mas, vol.1, issue.3

, INSERM U1037, 2016.

, Laboratoire d'hématologie

, UPS and CNRS

, Acute myeloid leukemia; miR-16; FLT3-ITD; STAT5; CDC25A; proliferation; of this receptor. First, we established by CHIP analysis that STAT5 is directly involved in FLT3-ITD-dependent CDC25A gene transcription. In addition, we determined that miR-16 expression is repressed by FLT3-ITD activity, and that STAT5 participates in this repression. In accordance with these results, miR-16 expression was significantly reduced in a panel of AML primary samples carrying the FLT3-ITD mutation when compared with FLT3wt cells. The expression of a miR-16 mimic reduced CDC25A protein and mRNA levels, and RNA interference-mediated down modulation of miR, Stéphane Manenti: stephane.manenti@inserm.fr Key words

. Finally, decreasing miR-16 expression partially restored the proliferation of cells treated with the FLT3 inhibitor AC220, while the expression of miR-16 mimic stopped this proliferation and induced monocytic differentiation of AML cells. In summary, we identified a FLT3-ITD/STAT5/miR-16/CDC25A axis essential for AML cell proliferation and differentiation

, STAT5 actually induced a dramatic decrease in CDC25A protein level, but inhibiting miR-16, which was modestly increased under these conditions (figure 4B)

, In the OCI-AML3 leukemic cell line, which expresses wild type FLT3, activating FLT3 with FLT3 ligand, or inhibiting the receptor with AC220, modified neither CDC25A protein nor the miR-16 level (Figure 4C-D). Overall, these data obtained in human leukemic cells suggest that several different signaling pathways operate in different cell lines to regulate CDC25A, This indicates that STAT5 regulation of CDC25A does not depend on miR-16 in this cell line

, MiR-16 regulates FLT3-ITD AML cell proliferation and differentiation Considering that we identified CDC25A as a master regulator of FLT3-ITD AML proliferation and differentiation, we decided to investigate whether this is also the case for miR-16. Expressing miR-16 mimic in MOLM-14 or MV4-11 cells for 72 hours significantly decreased their proliferation (figure 5A)

, Overexpressing miR-16 also reduced cell proliferation in this case, suggesting that targeting this pathway could overcome some of the resistance observed with FLT3-ITD kinase inhibitors (Figure 5A). In accordance with these results, the clonogenic potential of primary cells from a FLT3-ITD-positive patient was reduced when miR-16 was overexpressed, Down-regulating miR-16 partially restored proliferation of MOLM-14 or MV4-11 cells treated with the FLT3 inhibitor AC220 (Figure 5B)

, As seen in figure 5D, miR-16 expression induced differentiation of MOLM-14 cells, as indicated by increased expression of the cell surface differentiation marker CD11b. Interestingly, this was also the case in MOLM-14-TKD cells that are resistant to FLT3 inhibition, we then examined whether miR-16 down-regulation by FLT3-ITD was involved in the differentiation block of these cells

, suggesting that monocytic rather than granulocytic differentiation was induced by miR-16 in FLT3-ITD cells, 5E and F)

H. Döhner, D. J. Weisdorf, and C. D. Bloomfield, Acute myeloid leukemia, N Engl J Med, 2015.

E. Papaemmanuil, M. Gerstung, L. Bullinger, V. I. Gaidzik, P. Paschka et al., Genomic Classification and Prognosis in Acute Myeloid Leukemia, N Engl J Med, vol.374, issue.23, pp.2209-2221, 2016.

N. Daver, R. F. Schlenk, N. H. Russell, and M. J. Levis, Targeting FLT3 mutations in AML: review of current knowledge and evidence, Leukemia, vol.33, issue.2, pp.299-312, 2019.

R. M. Stone, S. J. Mandrekar, B. L. Sanford, K. Laumann, S. Geyer et al., Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation, N Engl J Med, vol.377, issue.5, pp.454-464, 2017.

J. E. Cortes, K. Samer, G. Khaled, A. E. Martinelli, S. Perl et al.,

K. Holmes, R. Kobayashi, N. Namuyinga, A. Ge, Y. Yver et al.,

, Levis. Efficacy and Safety of Single-Agent Quizartinib (Q), a Potent and Selective FLT3 Inhibitor (FLT3i), in Patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD

/. Relapsed and . Refractory, R/R) Acute Myeloid Leukemia (AML) Enrolled in the Global, Phase 3, Randomized Controlled Quantum-R Trial, Blood, vol.132, p.563, 2018.

M. Grundy, C. Seedhouse, T. Jones, L. Elmi, M. Hall et al., Predicting effective pro-apoptotic anti-leukaemic drug combinations using co-operative dynamic BH3 profiling, PLoS One, vol.13, issue.1, p.19068, 2018.

S. Bertoli, H. Boutzen, L. David, C. Larrue, F. Vergez et al., CDC25A governs proliferation and differentiation of FLT3-ITD acute myeloid leukemia, Oncotarget, vol.6, pp.38061-38078, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01594827

R. Boutros, V. Lobjois, and B. Ducommun, CDC25 phosphatases in cancer cells: key players? Good targets?, Nat Rev Cancer, vol.7, issue.7, pp.495-507, 2007.
URL : https://hal.archives-ouvertes.fr/hal-00317350

A. Fernandez-vidal, L. Ysebaert, C. Didier, R. Betous, D. Toni et al., Cell adhesion regulates CDC25A expression and proliferation in acute myeloid leukemia, Cancer Res, vol.66, issue.14, pp.7128-7163, 2006.
URL : https://hal.archives-ouvertes.fr/hal-00107359

A. Fernandez-vidal, A. Mazars, E. F. Gautier, G. Prévost, B. Payrastre et al., Upregulation of the CDC25A phosphatase down-stream of the NPM/ALK oncogene participates to anaplastic large cell lymphoma enhanced proliferation, Cell Cycle, vol.8, issue.9, pp.1373-1382, 2009.
URL : https://hal.archives-ouvertes.fr/hal-02666621

E. F. Gautier, M. Picard, C. Laurent, C. Marty, J. L. Villeval et al., The cell cycle regulator CDC25A is a target for JAK2V617F oncogene, Blood, vol.119, issue.5, pp.1190-1199, 2012.

A. Fernandez-vidal, A. Mazars, and S. Manenti, CDC25A: a rebel within the CDC25 phosphatases family?, Anticancer Agents Med Chem, vol.8, issue.8, pp.825-856, 2008.
URL : https://hal.archives-ouvertes.fr/hal-02657830

D. Ray and H. Kiyokawa, CDC25A phosphatase: a rate-limiting oncogene that determines genomic stability, Cancer Res, vol.68, issue.5, pp.1251-1254, 2008.

H. E. Pelish, B. B. Liau, I. I. Nitulescu, A. Tangpeerachaikul, Z. C. Poss et al.,

A. A. Bt, O. Fadeyi, A. L. Christie, K. Du, D. Banka et al., Mediator kinase inhibition further activates super-enhancer-associated genes in AML, Nature, vol.526, issue.7572, pp.273-276, 2015.

A. Rascle, J. A. Johnston, and B. Amati, Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5, Mol Cell Biol, vol.23, issue.12, pp.4162-73, 2003.

J. Pothof, N. S. Verkaik, W. Van-ijcken, E. A. Wiemer, V. T. Ta et al., MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response, EMBO J, vol.28, issue.14, pp.2090-2099, 2009.

K. T. Kim, A. P. Carroll, B. Mashkani, M. J. Cairns, D. Small et al., MicroRNA-16 is down-regulated in mutated FLT3 expressing murine myeloid FDC-P1 cells and interacts with Pim-1, PLoS One, 2012.

C. Larrue, E. Saland, F. Vergez, N. Serhan, E. Delabesse et al.,

T. J. Ma, S. Manenti, J. E. Sarry, and C. Récher, Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations, Mol Cancer Ther, vol.201, issue.10, pp.2364-73

E. Vigo, H. Müller, E. Prosperini, G. Hateboer, P. Cartwright et al.,

, phosphatase is a target of E2F and is required for efficient E2F-induced S phase, Mol Cell Biol, 1999.

K. Galaktionov, X. Chen, and D. Beach, Cdc25 cell-cycle phosphatase as a target of c-myc

, Nature, vol.382, issue.6591, pp.511-518, 1996.

B. Barré, A. Vigneron, and O. Coqueret, The STAT3 transcription factor is a target for the Myc and riboblastoma proteins on the Cdc25Apromoter, J Biol Chem, vol.280, issue.16, pp.15673-81, 2005.

P. J. Coffer, L. Koenderman, and R. P. De-groot, The role of STATs in myeloid differentiation and leukemia, Oncogene, vol.19, issue.21, pp.2511-2533, 2000.

K. D. Bunting, STAT5 signaling in normal and pathologic hematopoiesis, Front Biosci, vol.12, pp.2807-2827, 2007.

A. Rani and J. J. Murphy, STAT5 in Cancer and Immunity, J Interferon Cytokine Res, vol.36, issue.4, pp.226-263, 2016.

B. Groner, V. Von-manstein, and . Jak, Stat signaling and cancer: Opportunities, benefits and side effects of targeted inhibition, Mol Cell Endocrinol, vol.451, pp.1-14, 2017.

A. Shastri, G. Choudhary, M. Teixeira, S. Gordon-mitchell, N. Ramachandra et al.,

L. Bhattacharyya, S. Lopez, R. Pradhan, K. Giricz, O. Ravipati et al.,

R. , S. U. Will, B. Verma, and A. , Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells, J Clin Invest, vol.128, issue.12, pp.5479-5488, 2018.

D. Gerloff, R. Grundler, A. A. Wurm, D. Bräuer-hartmann, C. Katzerke et al.,

, network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia, Leukemia, vol.29, issue.3, pp.535-582, 2015.

A. Nogami, K. Okada, S. Ishida, H. Akiyama, Y. Umezawa et al.,

, Kinase Axis Enhances Cytotoxic Effects of Proteasome Inhibitors on FLT3-ITD-Positive AML Cells by Cooperatively Inhibiting the mTORC1/4EBP1/S6K/Mcl-1 Pathway, 2019.

B. Wingelhofer, B. Maurer, E. C. Heyes, A. A. Cumaraswamy, A. Berger-becvar et al.,

, Pharmacologic inhibition of STAT5 in acute myeloid leukemia, Leukemia, vol.32, issue.5, pp.1135-1146, 2018.

G. Li, K. L. Miskimen, Z. Wang, X. Y. Xie, J. Brenzovich et al.,

, STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease, Blood, vol.115, issue.7, pp.1416-1440, 2010.

T. Liu, Z. Xu, D. Ou, J. Liu, and J. Zhang, The miR-15a/16 gene cluster in human cancer: A systematic review, J Cell Physiol, vol.234, issue.5, pp.5496-5506, 2019.

T. Nosaka, T. Kawashima, K. Misawa, K. Ikuta, A. L. Mui et al., STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells, EMBO J, 1999.

M. Mizuki, J. Schwable, C. Steur, C. Choudhary, S. Agrawal et al., Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations, Blood, vol.101, issue.8, pp.3164-73, 2003.

S. Kasar, E. Salerno, Y. Yuan, C. Underbayev, D. Vollenweider et al., Systemic in vivo lentiviral delivery of miR

, Genes Immun, vol.13, issue.2, pp.109-128, 2012.

G. Cutrona, S. Matis, M. Colombo, C. Massucco, G. Baio et al.,

A. G. Gentile, M. Neumaier, C. E. Reverberi, D. Massara, R. Boccardo et al.,

M. , Z. S. Truini, M. Tassone, P. Calabrese, M. Negrini et al., Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy, Leukemia, vol.31, issue.9, pp.1894-1904, 2017.

M. S. Beg, A. J. Brenner, J. Sachdev, M. Borad, Y. K. Kang et al., Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors, Invest New Drugs, vol.35, issue.2, pp.180-188, 2017.

S. M. Gao, J. Yang, C. Chen, S. Zhang, C. Y. Xing et al., miR-15a/16-1 enhances retinoic acid-mediated differentiation of leukemic cells and is up-regulated by retinoic acid, Leuk Lymphoma, vol.52, issue.12, pp.2365-71, 2011.

H. G. Moon, J. Yang, Y. Zheng, and Y. Jin, miR-15a/16 regulates macrophage phagocytosis after bacterial infection, J Immunol, vol.193, issue.9, pp.4558-67, 2014.

A. Cimmino, G. A. Calin, M. Fabbri, M. V. Iorio, M. Ferracin et al.,

Z. S. Ri, M. Dono, L. Rassenti, H. Alder, S. Volinia et al., miR-15 and miR-16 induce apoptosis by targeting BCL2, Proc Natl Acad Sci, vol.102, issue.39, pp.13944-13953, 2005.

A. H. Wei, S. A. Strickland, J. Z. Hou, W. Fiedler, T. L. Lin et al.,

M. , L. S. Chyla, B. Popovic, R. Salem, A. H. Agarwal et al., Venetoclax Combined With Low-Dose Cytarabine for Previously Untreated Patients With Acute Myeloid Leukemia: Results From a Phase Ib/II Study, J Clin Oncol, 2019.

R. Singh-mali, E. A. Lasater, K. Doyle, R. Malla, E. Boghaert et al.,

. Flt3-itd, Activation Mediates Resistance to the BCL-2 Selective Antagonist, Venetoclax, in FLT3-ITD Mutant AML Models, Blood, vol.130, p.1348, 2017.

, miR-16 level is dependent on FLT3-ITD activity and STAT5 in AML cells A. MOLM-14 and MV4-11 cells were treated for 2 hours with the FLT3 inhibitor AC220 (2nM) and the miR-16 level was analyzed by RT-qPCR, vol.3

B. , Basal miR-16 levels were analyzed by RT-qPCR and normalized to a control (MOLM14)

C. , MV4-11 cells were transfected for 24 hours with STAT5A/B siRNA and the miR-16 level was analyzed by RT-qPCR

D. Molm, -14 and MV4-11 cells were treated for 2h with ERK or Akt inhibitors (50nM and 5µM respectively) and the miR-16 level was analyzed by RT-qPCR

E. , MOLM-14 and MV4-11 cells were transfected for 24 hours with a premiR-16 and the CDC25A

F. Molm, -14 and MV4-11 cells were transfected for 24 hours with a miR-16 inhibitor and treated for 2 hours with AC220 (2nM), the CDC25A and Pim1 protein levels were analyzed by western blot

G. , MV4-11 cells were transfected for 24 hours with a miR-16 inhibitor and STAT5A/B siRNA, and the CDC25A protein level was analyzed by western blot

, These results are representative of at least 3 independent experiments. Actin was used as a loading control in the western blot experiments. ns: non-specific

, The STAT5/miR-16/CDC25A axis is specific to FLT3-ITD positive cells A. HEL cells were transfected for 24 hours with a miR-16 inhibitor and STAT5A/B siRNA. CDC25A and STAT5 protein levels were analyzed by western blot, Figure, vol.4

B. , HEL cells were transfected for 24 hours with STAT5A/B siRNA and miR-16 level was analyzed by RT-qPCR

C. , OCI-AML3 cells were treated for 2 hours with the FLT3 inhibitor AC220 (2nM) and/or FLT3 ligand (6nM), and the CDC25A protein level was analyzed by western blot

, OCI-AML3 cells were treated for 2 hours with the FLT3 inhibitor AC220 (2nM) and/or FLT3 ligand (6nM) and the miR-16 level was analyzed by RT-qPCR

, These results are representative of at least 3 independent experiments. Actin was used as a loading control in the western blot experiments. ns: non-specific

, miR-16 inhibits cell proliferation in FLT3-ITD cell lines and primary cells, and triggers monocytic differentiation in FLT3-ITD AML cells A. MOLM-14 and MV4-11 (FLT3-ITD), vol.5

B. , MOLM-14 and MV4-11 cells were transfected with pre-miRcontrol or pre-miR-16 as in A, and then treated with AC220 (2 nM) 24 hours after transfection. 72 hours after transfection

C. , Primary cells from three AML patients were transduced with a lentiviral vector expressing a scrambled shRNA (Ctrl, black bars) or the miR-16 (miR-16, grey bars), and clonogenic potential was assessed by colony forming assay 7 days after transduction (left panel). Transduction efficiency was assessed by RT-qPCR after 3 days

D. Molm-14, OCI-AML3, MOLM14-TKD or MV4-11 cells were transfected with pre-miRcontrol or pre-miR-16 as in A, and then labeled with anti CD11 (D) and CD14 (E) or anti CD15

, F) antibodies in order to monitor their differentiation state. Annexin V labeling was performed in of NuPAGE® LDS Sample Buffer (Novex, Life Technologies), sonicated for 4x7 seconds, and boiled for 3 minutes, Proteins were then resolved on NuPAGE®, pp.4-12

, After four additional washes, detection was achieved with ECL TM or ECL TM prime western blotting detection reagents (GE Healthcare). The antibodies used were: monoclonal anti-CDC25A (F-6) and anti-Pim1 (12H8) from Santa Cruz; monoclonal antiphospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (E10) and polyclonal anti-phospho-STAT5 (Tyr 694), anti-STAT5, anti-p44/42 MAPK, anti-Akt 1/2/3, anti-phospho-Ser473 Akt (D9E) XP, Bis-Tris Gels and transferred to nitrocellulose membrane. The membrane was saturated for 1 hour in Tris Buffer Saline with Tween 0.1% (TBS-T) containing 5% non-fat milk

. Rt-qpcr, Cells were lysed in TRIzol (Invitrogen) and total RNA was then extracted according to the manufacturer's instructions. For gene expression analysis, cDNA was generated with the SuperScript III First-Strand Synthesis System for RT-PCR (Invitrogen) according to the manufacturer's instructions. The PCR was performed with TaqMan® Gene Expression Master Mix (Applied Biosystems) with 10ng of cDNA, The primer used was Hs00947994_m1 (Applied Biosystem) for CDC25A. GUSB (Hs00939627_m1) and B2M (Hs00984230_m1) were used as housekeeping genes

, For mature micro-RNA expression analysis, cDNA was generated using the TaqMan® micro-RNA reverse transcription kit (Applied Biosystems), and PCR was performed using the TaqMan® Universal Master Mix with UNG (Applied Biosystems), and the TaqMan microRNA assays (Applied Biosystems) according to the manufacturer's instructions. The primers used were miR, p.16

, U6 snRNA (assay 001973) as a control. Results were analyzed with the StepOne TM software v2.2.2 (Applied Biosystems) using the conventional ??Ct method, PCR was carried out on a StepOne TM (Applied Biosystems)

, RNA transfection

, Cells (2 x 10 6 ) were re-suspended in 100 ?l of resuspension buffer, and various doses of RNA were added. RNA sequences were: specific STAT5A and STAT5B siRNA (ON-TARGETplus SMARTpool, human STAT5A and STAT5B, Dharmacon) or siRNA control (sigenome control pool non targeting #2, or ON-TARGETplus control pool, Dharmacon), anti-miR control or anti-miR-16 (Life Technologies), and pre-microRNA negative control or pre-microRNA-16 (Life Technologies). Cells were then transfected with the nucleofector device (program 5 for MOLM14, MV4-11 and OCI-AML3 cell lines, Leukemic cell lines were transfected with the Neon transfection system (Life Technologies)

, Patient AML samples used in this work were obtained after informed consent in accordance with the Declaration of Helsinki and were stored in the HIMIP collection, pp.2008-307

, All were diagnosed at the Department of Hematology of Toulouse University Hospital. The patients' characteristics are listed in Supplementary Table 2, collection 1) and a transfer agreement was obtained (AC 2008-129) after approval by the ethics committees

, MV411 cells were transfected for 24 hours with STAT5A/B siRNA and treated with D actinomycin (3µg/ml) for the indicated times. The CDC25A mRNA level was analyzed by RT-qPCR