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, the Association pour la Recherche contre le Cancer (ARC) (Fondation ARC libre 2012), and the regional PHRC AOR07014. The program, sequencing (AO9102LS), the Association de recherche sur la moelle osseuse (ARMO)

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, Catherine Lacout, vol.6, p.11

, Dijon 21000, France. 2 INSERM, UMR 1231, Laboratory of Excellence Ligue National contre le Cancer, Dijon 21000, France. 3 Department of Biomedicine, Experimental Hematology, vol.20, p.4031

, Gustave Roussy, Villejuif 94800, France. 6 INSERM, UMR 1170, Laboratory of Excellence GR-Ex

, CNRS UMR, vol.8251, p.75013

B. Vancouver, C. Bc, . Cnrs, D. Épigénétique, and . Cellulaire, 12 Département Hospitalo-Universitaire DHU PROTECT, Paris 75010, France. 13 Centre Georges François Leclerc (CGFL), Dijon 21000, France. 14 Scientific Cooperation Foundation (FCS) of, Paris 75013 Cedex 13, vol.75013

. Nature-communications-|, , vol.9, 2018.

. Reagents, ) and the oligonucleotide control were synthetized by OncoGenex Pharmaceuticals. AG490 was purchased from Invivogen (100 µM), 427, a second-generation antisense oligonucleotide inhibitor (Patent PCT no. 10/605, vol.498, 2005.

, Antibodies for flow cytometry included anti-CD34 PE-Cy7 (dilution 5:100, clone 8G12, #348811), -CD45 APC (dilution 20:100, clone HI30, #555485), -Mouse IgG FITC purchased from BD Biosciences and anti-HSP27 FITC (dilution 1:200, clone G3.1, SPA-800FI), -HSP70 FITC (SPA-810FI, clone C92F3A-5, dilution 1:100), -HSP90 Alexa 488 (dilution 1:10, clone AC88, SPA830-488) from Enzo Life Sciences. Secondary antibodies were purchased from Jackson Immunoresearch Laboratories. The two siRNAs against HSP27, -HSP70 (dilution 1:1000, clone C92F3A-5, SPA-810) and -HSP90 (dilution 1:1000, clone AC88

, Uncropped blots are presented in Supplementary Fig. 7, 8. Protein interaction studies. For in vitro interaction experiments, we used biolayer interferometry technology (Octet Red, Forté-Bio). Recombinant HSP27 (ADI-ESP-715, Enzo-Life Sciences (produced in Escherichia coli, low endotoxin)) was desalted (Zeba? Spin Desalting Columns, 7K molecular-weight cutoff, 0.5 ml (1034-1164, Fisher Scientific)) and biotinylated at a molar ratio biotin/protein (3:1) for 30, Cell lines and transfections. The JAK2V617F-positive human leukaemic cell line HEL92.1.7 (ACC-11, from DSMZ) and SET-2 (ACC-608, from DSMZ)

, EnzoLife Sciences)) were analysed after association (600 s) and dissociation (600 s) steps at 26°C. The specificity of the BLI experiments was tested and validated as shown in Supplementary Fig. 4d-f. For in vitro immunoprecipitation, recombinant proteins were produced using TNT Quick Coupled Transcription/Transcription System (L1170, Promega) as follows: 1 mg of template plasmid DNA was added to the reaction mixture, which was afterwards incubated at 30°C for 90 min. The in vitro translated proteins were incubated for 15 min at 37°C in buffer (Hepes pH 7.4 10 mM, NaCl 25 mM, MgCl 2 5 mM, MnCl 2 5 mM, dithiothreitol (DTT) 1 mM, protease and phosphatase inhibitors) and then subjected to immunoprecipitation for 1 h and 30 min at RT using an anti-mouse HSP27 antibody (2 µg, clone G3.1, SPA-800, Enzo Life Sciences) or a mouse IgG (serum, Excess Biotin was removed using Zeba? Spin Desalting Columns. Biotinylated recombinant HSP27 was used as a ligand and immobilized at 10 ?g ml ?1 on streptavidin biosensors after dilution in phosphate-buffered saline (PBS; 600 s). Interactions with desalted analytes diluted in PBS at 125 nM (recombinant STAT5a/b (TP305753 and TP309429 respectively, Origen), JAK2 (TP320503, Origen) or the RING domain of CBP (gift from Dr. Rodrigues-Lima used as a negative control 74 or crystallin alpha B as a positive control, vol.5381, p.5

, ) or a mouse IgG as a negative control (serum, vol.5381

, For shRNA experiments, the sequence for shRNA targeting human HSP27 (forward-gatcccc (GATCACCATCCCAGT-CACCTT, sens) ttcaagaga (AAGGTGACTGGGATGGTGATC, antisens) tttttggaaa and reverse-agcttttccaaaaa (GATCACCATCCCAGTCACCTT, sens) tctcttgaa (AAGGTGACTGGGATGGTGATC, antisens) ggg) (Eurofins Genomics) was cloned in the pRRLsin-PGK-eGFP-WPRE vector (Addgene, #12252) using a shuttle vector pH1 and the ligase T4 DNA (M0202, Lentivirus particles were produced in HEK293T cells after transfection of the cells with the plasmids PRRL-HSP27 (15 ?g), p.2

, NaF 10 mM) in the presence or absence of ATP (250 µM, #9804, Cell Signalling Technology) and the reaction was stopped by adding 2× Laemmli buffer. In vitro transcription and translation reactions were performed using TNT Quick Coupled Transcription/Transcription System (L1170, Promega) as the de-phosphorylation assay, a phosphorylation kinase assay JAK2/STAT5 last injection (Fig. 1a). For the JAK2V617F murine model, bone marrow cells (2 × 10 6 per recipient) from 2-month-old female C57BL/6J mice (control mice, Harlan Laboratories) and SclCreend of the experiment, the mice were killed, and spleens were weighed and stored at ?20°C. The female mice had free access to food and water, G (5 ?g, 12259, Addgene) using the calcium chloride transfection method. Viral particles were concentrated by ultracentrifugation (45 min, 20,000 × g). 10 mM

, At the end of the study, spleens were weighed, measured and stored in 4% paraformaldehyde for histopathology studies or frozen at ?20°C for western blot analysis. The concentration of HSP27 in serum from control mice was measured by ELISA at 3 months after the transplantation. For bone marrow analysis, femurs were collected, fixed in 4% phosphate-buffer formalin, embedded in paraffin and sectioned. Tissue sections were stained with haematoxylin and eosin for morphology analysis, which was performed in a blinded fashion. Images were organized in folders identified by letters by one person and quantified by another. A minimum of n =5-9 mice were used for each experiment

, Patient's samples. Patient samples (serum, blood and histological section) were obtained from the University Hospital of Dijon and Gustave Roussy (France)

, After RBC lysis, cells were pelleted by centrifugation, resuspended in FACS staining medium (PBS+5% FCS) and filtered through 100 µm cell strainer (Falcon, #352360). Cells were stained with biotin-labelled mouse lineage antibodies (anti-Ter119 (clone Ter119, #116203), anti-B220 (clone RA36B2, #103203), To determine the number of megakaryocytes in the bone marrow and spleen, the cells were isolated and resuspended in lysing buffer (ACK Lysing Buffer

, After staining, cells were washed with FACS staining medium, pelleted down by centrifugation (1200 rpm, 5 min) and stained with streptavidin Pacific-Blue Conjugate (#1094418, Invitrogen) for 30 min followed by second wash with FACS staining medium. The cells were then pelleted down by centrifugation (1200 rpm, 5 min), resuspended in FACS staining medium containing SYTOX blue dead cell stain (S34857, Life Technologies) and acquired on LSRFortessa TM (BD Biosciences) (FACs gating strategy, Supplementary Fig. 9a). Peripheral blood mononuclear cells (PBMCs) from peripheral blood or cord blood were collected in EDTA tubes and isolated by Ficoll-Paque density gradient centrifugation. PBMCs were immuno-stained with anti-CD34-PE-Cy7 and anti-CD45-APC antibodies in stain Buffer (BD Biosciences) for 45 min and washed. The cells were fixed and permeabilized in commercial solution (BD Biosciences) and then stained using anti-HSP FITC/Alexa 488 or anti-mouse IgG FITC control antibody for 30 min. After washing, the cells were analysed by flow cytometry. The CD45 low /CD34 high population was gated and the median fluorescence intensities of intracellular HSPs were evaluated (FACs gating strategy, Supplementary Fig. 9b). (Amgen, anti-Mac1 (clone M1/70, #101203) and APC-Cy7 anti-c-kit (clone 2B8, #105825), PE-Cy7 anti-sca-1 (clone D7, #108113), APC anti-CD150 (clone TC15-12F12.2, #115909) and PE anti-CD41 (clone MWReg30, #133905), vol.9, p.1431, 2018.

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