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JAK2 V617F mutation is frequently identified in myeloproliferative neoplasms (MPN). Additional somatic variants are supposed to contribute to bone marrow fibrosis or acute myeloid leukemia evolution. One of these mutations affects SRSF2, a gene encoding a component of the splicing machinery. To investigate how Jak2 V617F and Srsf2 P95H mutations interact in the hematopoietic tissue, we generated conditional knock-in mice in which the two mutations were expressed upon the control of Scl gene. Our study shows that Srsf2 P95H mutation initially exhibits limited effect on Jak2 V617F polycythemia and thrombocytosis but induces a delay in myelofibrosis development and protect hematopoietic stem cell from exhaustion observed after serial transplantation in Jak2 V617F single mutant cells. We focused on megakaryocyte (MK), implied in fibrosis development and found that Srsf2P95H partially reversed MKabnormalities induced by Jak2 V617F (cell size, normalized ploidy and expression of c-Mpl). Analysis of c-Mpl/Jak2 signaling with mass cytometry revealed a slight reduced proportion of MK expressing high levels of P-Stat5 in case of Srsf2 P95H co-occurrence with Jak2 V617F while treatment with high dose of the thrombopoietin-mimetic romiplostim in mice transplanted with wild-type or Srsf2 P95H bone marrow cells confirms the negative impact of Srsf2 P95H on fibrosis development. Gene expression analysis on sorted MK confirms down-regulation of Jak/Stat signaling pathway induced by Srsf2 P95H and reveals that Srsf2 P95H mutation more frequently induces exon 14 skipping of Jak2 mRNA. These result was confirmed in granulocytes samples from patients with JAK2 V617F MPN with associated SRSF2 P95H mutation., La mutation JAK2 V617F est fréquemment observée en cas de néoplasme myéloprolifératif (NMP). D’autres mutations somatiques peuvent être associées et sont corrélées au stade myélofibrotique ou à une évolution en leucémie aigüe. L’une de ces mutations touche le gène SRSF2, codant pour une protéine du complexe d’épissage. Pour étudier l’interaction entre les mutations Jak2 V617F et Srsf2 P95H dans le tissu hématopoïétique, nous avons généré un modèle murin knock-in conditionnel des deux mutations s’exprimant sous le contrôle du gène Scl. Notre étude montre que Srsf2 P95H limite peu le développement de la polyglobulie et de la thrombocytose induites par Jak2 V617F mais freine l’évolution vers une fibrose médullaire et protège les cellules souches hématopoïétiques de l’épuisement en transplantations sériées. L’étude des mégacaryocytes (MK), impliqués dans le processus fibrotique, montre que Srsf2 P95H induit une quasi-normalisation des anomalies induites par Jak2 V617F (taille, ploïdisation, expression de c-Mpl). L’analyse de la signalisation c-Mpl/Jak2 par cytométrie de masse révèle une discrète diminution de la proportion de MK exprimant de haut niveau de P-Stat5 en cas de mutation Srsf2 P95H associée à Jak2 V617F tandis que l’injection d’un agoniste de la thrombopoïetine à fortes doses confirme l’impact négatif de Srsf2 P95H sur le développement de la fibrose. L’étude de l’expression génique de MK triés confirme l’altération de la voie Jak/Stat induite par Srsf2 P95H et révèle que Srsf2 P95H induit plus fréquemment une perte de l’exon 14 (incluant la mutation V617F) de l’ARNm de Jak2. Ce résultat est confirmé sur des échantillons de granulocytes de patients atteints de NMP JAK2 V617F avec mutation SRSF2 P95H associée.

[Purpose] Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML)., [Methods] This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor., [Results] Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm., [Conclusion] Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36)., Supported by Oryzon Genomics and IPT-2012-0673-010000 of the INNPACTO program of the Spanish Ministry of Economy and Competitiveness, with contribution of Fondo Europeo de Desarrollo Regional (FEDER) from the European Union and CDTI_CIIP-20131005/EUROSTAR_E18159. T.C.P.S. is supported by Cancer Research UK Grant No. C5759/A20971. R.P. is supported by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre.

International audience; Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except forEscherichia coliandEnterococcusspp., which became dominant. Both the alpha and beta-diversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase ofE. coliandEnterococcusspp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved alpha-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients' outcome.

Non-classical monocyte subsets may derive from classical monocyte differentiation and the proportion of each subset is tightly controlled. Deregulation of this repartition is observed in diverse human diseases, including chronic myelomonocytic leukemia (CMML) in which non-classical monocyte numbers are significantly decreased relative to healthy controls. Here, we identify a down-regulation of hsa-miR-150 through methylation of a lineage-specific promoter in CMML monocytes. Mir150 knock-out mice demonstrate a cell-autonomous defect in non-classical monocytes. Our pulldown experiments point to Ten-Eleven-Translocation-3 (TET3) mRNA as a hsa-miR-150 target in classical human monocytes. We show that Tet3 knockout mice generate an increased number of non-classical monocytes. Our results identify the miR-150/TET3 axis as being involved in the generation of non-classical monocytes., A decrease in the fraction of non-classical monocytes is a hallmark of chronic myelomonocytic leukaemia. Taking advantage of this abnormal situation, the authors identify a mechanistic link between miR-150 and TET3 as being involved in monocyte subset generation.

Johanna Mondesir1,2 Christophe Willekens3–5 Mehdi Touat6,7 Stéphane de Botton3–5 1Service d’Immunopathologie Clinique, Hôpital Saint Louis, 2CNRS UMR8104, INSERM U1016, Institut Cochin, Université Paris Descartes, Paris, 3Gustave Roussy, Université Paris-Saclay, Service d’Hématologie Clinique, 4INSERM U1170, Gustave Roussy, Université Paris-Saclay, Villejuif, 5Faculté de médecine Paris-Sud, Kremlin-Bicêtre, 6AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière – Charles Foix, Service de Neurologie 2-Mazarin, Paris, 7Gustave Roussy, Université Paris‑Saclay, Département d’Innovation Thérapeutique et d’Essais Précoces, Villejuif, France Abstract: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies. Somatic point mutations inIDH1/2confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Indeed, high levels of D-2HG inhibit α-ketoglutarate-dependent dioxygenases, including histone and DNA demethylases, leading to histone and DNA hypermethylation and finally a block in cell differentiation. Furthermore, D-2HG is a biomarker suitable for the detection ofIDH1/2mutations at diagnosis and predictive of the clinical response. Finally, mutant-IDH1/2 enzymes inhibitors have entered clinical trials for patients withIDH1/2mutations and represent a novel drug class for targeted therapy. Keywords: tumor metabolism, epigenetic, oncogene, IDH1, IDH2, glioma, acute myeloid leukemia, 2-HG, targeted therapies

International audience; We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long-term AIHA response. Am. J. Hematol. 90:204–207, 2015.