Contributors: Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC); Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC); Université de Rennes (UR)-Etablissement français du sang Rennes (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM); Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Pontchaillou; Centre de Recherches en Cancérologie de Toulouse (CRCT); Université Toulouse III - Paul Sabatier (UT3); Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Institut de génétique humaine (IGH); Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); Université de Toulouse (UT); Institut de Génétique et Développement de Rennes (IGDR); Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); H2P2 - Histo Pathologie Hight Precision (H2P2); Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST); Université de Limoges (UNILIM)-Université de Limoges (UNILIM); This work was funded by an internal grant from the Hematology Laboratory, CHU deRennes, and Région GO Ligue contre le Cancer. MH has received a doctoral fellowshipfrom FHU CAMIn, Ligue Contre le Cancer/Comité d’Ile et Vilaine. AP received a PhDfellowship from Région Bretagne and Ligue Nationale contre le Cancer.Immunofluorescence studies were performed at the Microscopy Rennes ImagingCenter (MRic-ALMF) and in the H2P2 facility, both of which are members of the UMS6480 Biosit (Rennes, France) and the French national France-BioImaginginfrastructure network funded by the French Research Agency (ANR-10-INBS-04). Cellsorting was performed at the Biosit Flow Cytometry and the CytomeTRI cell sortingfacilities (UMS6480 Biosit). We are indebted to the Centre de Ressources Biologiques(CRB)-Santé (BB-0033-00056, http://www.crbsante-rennes.com) at Rennes UniversityMedical Center for its help with processing biological samples, and we also thankseveral clinicians and patients for providing samples for research purposes. We thankthe MMRF for sharing the RNA sequencing and clinical data for patients enrolled in theCoMMpass study via the MMRF genomics portal.; ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
نبذة مختصرة : International audience ; The differentiation of B cells into plasmablasts (PBs) and then plasma cells (PCs) is associated with extensive cell reprogramming and new cell functions. By using specific inhibition strategies (including a novel morpholino RNA antisense approach), we found that early, sustained upregulation of the proviral integrations of Moloney virus 2 (PIM2) kinase is a pivotal event during human B cell in vitro differentiation and then continues in mature normal and malignant PCs in the bone marrow. In particular, PIM2 sustained the G1/S transition by acting on CDC25A and p27Kip1 and hindering caspase 3-driven apoptosis through BAD phosphorylation and cytoplasmic stabilization of p21Cip1. In PCs, interleukin-6 triggered PIM2 expression, resulting in anti-apoptotic effects on which malignant PCs were particularly dependent. In multiple myeloma, pan-PIM and MCL1 inhibitors displayed synergistic activity. Our results highlight a cell-autonomous function that links kinase activity to the PBs’ newly acquired secretion ability and the adaptability observed in both normal and malignant PCs, and finally should prompt the reconsideration of PIM2 as a therapeutic target in multiple myeloma.
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