2. Academic Validation
  3. PIM2 kinase has a pivotal role in plasmablast generation and plasma cell survival, opening up novel treatment options in myeloma

PIM2 kinase has a pivotal role in plasmablast generation and plasma cell survival, opening up novel treatment options in myeloma

  • Blood. 2022 Apr 14;139(15):2316-2337. doi: 10.1182/blood.2021014011.
Marion Haas 1 2,  Gersende Caron 1 2,  Fabrice Chatonnet 1 2,  Stéphane Manenti 3,  Elina Alaterre 4,  Julie Devin 4,  Céline Delaloy 1,  Giulia Bertolin 5,  Roselyne Viel 6,  Amandine Pignarre 1 2,  Francisco Llamas-Gutierrez 7,  Anne Marchalot 8,  Olivier Decaux 1 9,  Karin Tarte 1 2,  Laurent Delpy 8,  Jérôme Moreaux 4,  Thierry Fest 1 2
Affiliations

Affiliations

  • 1 Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, Unité Mixte de Recherche (UMR)_S1236, Rennes, France.
  • 2 Laboratoire d'hématologie et immunologie, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France.
  • 3 Université de Toulouse, Centre National de la Recherche Scientifique (CNRS) Equipe de Recherche Labellisée (ERL) 5294, INSERM U1037, Centre de Lutte Contre le Cancer, Toulouse, France.
  • 4 Institut de Génétique Humaine, UMR 9002 CNRS-UM, Pôle de biologie, Centre Hospitalier Universitaire, Montpellier, France.
  • 5 Université de Rennes, CNRS, Institut de Génétique & Développement de Rennes, UMR 6290, Rennes, France.
  • 6 Plateforme H2P2, Rennes, France.
  • 7 Laboratoire d'Anatomie Pathologique, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France.
  • 8 Université de Limoges, UMR CNRS 7276, INSERM U1262, Limoges, France; and.
  • 9 Service d'hématologie clinique, Centre Hospitalier Universitaire, Rennes, France.
PMID: 35108359 DOI: 10.1182/blood.2021014011
Abstract

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 antiapoptotic effects on which malignant PCs were particularly dependent. In multiple myeloma, pan-PIM and myeloid cell leukemia-1 (MCL1) inhibitors displayed synergistic activity. Our results highlight a cell-autonomous function that links kinase activity to the newly acquired secretion ability of the PBs and the adaptability observed in both normal and malignant PCs. These findings should finally prompt the reconsideration of PIM2 as a therapeutic target in multiple myeloma.

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