Pivotal role of PIM2 kinase in plasmablast generation and plasma cell survival, opening new treatment options in myeloma

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.