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, We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-kB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment, Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs, vol.128, pp.2694-2707, 2016.
, Institut de Recherches sur le Cancer de Lille, c 12 BPDCN samples, c 65 AML samples (including different French-American-British subtypes: 25 M0, 11 M1, 10 M2, 1 M3, 11 M4, 6 M5, and 1 M6) (Unité, vol.837, 1151.
shtml) based on the expression of cholesterol homeostasis and LXR-related genes, Data were analyzed using dChip software ,
, Quantitative RT-PCR analysis Transcription of LXR target genes (ABCA1, ABCG1) and genes coding proteins involved in the intrinsic apoptosis (BCL2, BAK1, BAX) was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR)
, ) of T0901317 (total experimental dose, 30 or 60 mg/kg, respectively) or with dimethyl sulfoxide (DMSO)/phosphate-buffered saline (PBS) control solution. Mouse monitoring and quantification of BPDCN cell infiltrate were described in supplemental Methods. Experimentation (#11007R) was approved by our local ethics committee (#58, approved by the French Ministry of Higher Education and Research) and conducted in accordance with the European Union Directive 2010/63. Statistical analysis Statistical analyses were performed by GraphPad Prism version 6 (GraphPad Software, ) were used. imager and BIO-1D advanced software (Vilber-Lourmat
) for helpful discussions on cholesterol metabolism, the Cytology laboratory of the Etablissement Français du Sang Bourgogne Franche-Comté (BFC), for blood cell and platelet counts, Sarah Odrion, and Alexis Varin for editorial assistance, the Agence Nationale de la Recherche, 2015. ,
, via the Bonus Qualité Recherche BFC)
, Authorship Contribution: A.C. performed most of the experiments, collected, assembled, and analyzed data, performed statistical analysis, and wrote the manuscript
performed cholesterol efflux experiments and helped to write the manuscript ,
performed transcriptomic experiments and analysis; C.C. performed cell death analysis by flow cytometry, some immunoblotting, and qRT-PCR experiments ,
performed some confocal microscopy experiments ,
performed cell cycle experiments ,
performed and supported in vivo experiments ,
commented on the manuscript and helped to write it ,
,
commented on the manuscript and provided major funding support ,
provided study material, collected data, and helped to write the manuscript; and P.S. supervised research, analyzed data, and wrote the manuscript. Conflict-of-interest disclosure: The authors declare no competing financial interests. The current affiliation for B.L. is Université Pierre et Marie Curie, Correspondence: Philippe Saas, EFS BFC ,
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