Published January 2, 2025
| Version v1
Journal article
PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression
Contributors
Others:
- 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 méditerranéen de médecine moléculaire (C3M) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UniCA)
- 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)-OmégaHealth (ΩHealth) ; Université de Limoges (UNILIM)-Université de Limoges (UNILIM)
- Centre Hospitalier Universitaire d'Angers (CHU Angers) ; PRES Université Nantes Angers Le Mans (UNAM)
- Institut de génétique humaine (IGH) ; Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
- We thank all members of the Fest Laboratory for helpful discussion, J. Destin for technical assistance and F. Jouan for mouse colony management. Cell sorting was performed at the Biosit Flow Cytometry and the CytomeTRI cell sorting facilities (UMS6480 Biosit). Immunofluorescence studies were performed in the H2P2 facility, a member of the UMS 6480 Biosit (Rennes, France) and the French National France-BioImaging infrastructure network funded by the French Research Agency (ANR-10-INBS-0004). We gratefully acknowledge funding from "Fondation ARC" the "Programmes labellisés" (PGA) 2022 N° ARCPGA2021120004244_4856, the Internal grant from the Hematology Laboratory, CHU de Rennes, the ANR Carnot-CALYM program funded the purchase of NGS mice. M.H. has received a doctoral fellowship from FHU CAMIn, Ligue Contre le Cancer/Comité d'Ile et Vilaine. M.H. is supported by a "CCA–Inserm-Bettencourt Schueller" Fund. A.J.'s team was supported by Inserm and by "Fondation ARC" Equipe labellisée 2022–2025.
- ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)
Description
Our study explores the complex dynamics of the integrated stress response (ISR) axis, highlighting PIM2 kinase's critical role and its interaction with the BCL2 protein family, uncovering key mechanisms of cell survival and tumor progression. Elevated PIM2 expression, a marker of various cancers, often correlates with disease aggressiveness. Using a model of normal and malignant plasma cells, we show that inhibiting PIM2 kinase inhibits phosphorylated BAD production and activates ISR-mediated NOXA expression. This shift towards MCL1 dependence underscores the synergy achieved through combined PIM/MCL1 inhibition, driven largely by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth-a response reversed by ISR-specific inhibition and upregulation of genes linked to tumor cell dissemination. This work elucidates the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, especially in tumors with elevated PIM2 expression.
Abstract
International audienceAdditional details
Identifiers
- URL
- https://hal.science/hal-04883435
- URN
- urn:oai:HAL:hal-04883435v1
Origin repository
- Origin repository
- UNICA