生物
多发性骨髓瘤
等离子体电池
癌症研究
激酶
细胞凋亡
下调和上调
细胞生物学
细胞生长
免疫学
作者
Marion Haas,Gersende Caron,Fabrice Chatonnet,Stephane Manenti,Elina Alaterre,Julie Devin,Céline Delaloy,Giulia Bertolin,Roselyne Viel,Amandine Pignarre,Francisco Llamas Gutierrez,Anne Marchalot,Olivier Decaux,Karin Tarte,Laurent Delpy,Jérôme Moreaux,Thierry Fest
出处
期刊:Blood
[American Society of Hematology]
日期:2022-02-02
标识
DOI:10.1182/blood.2021014011
摘要
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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