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

Haas, Marion; Caron, Gersende; Chatonnet, Fabrice; Manenti, Stéphane; Alaterre, Elina; Devin, Julie; Delaloy, Céline; Bertolin, Giulia; Viel, Roselyne; Pignarre, Amandine; Gutierrez, Francisco Llamas; Marchalot, Anne; Decaux, Olivier; Tarte, Karin; Delpy, Laurent; Moreaux, Jérôme; Fest, Thierry

doi:10.1182/blood.2021014011

Cited by 8 publications

(10 citation statements)

References 57 publications

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“…We therefore focused our attention on 24 genes which predominantly or selectively affected PB differentiation ( Figure 1C ). This gene set included the major factors known to be important for plasma cell differentiation: transcription factors ( Prdm1 (BLIMP1), Irf4 , Pou2af1 (OBF-1), c-Myc , Sp3 , Tcf3 (E2A) and Stat3 ) ( 9 , 28 – 33 ), epigenetic factor Arid3a ( 34 ), kinase Pim2 ( 35 ), chaperone Hsp90b1 (GRP94) ( 36 ), p38 kinase Mapk14 ( 37 ), and Ern1 , encoding IRE1α, the principal UPR ER stress sensor active in plasma cells ( 38 ). Further hits, previously unknown to play a role in plasma cell differentiation (indicated with an asterisk in Figure 1D ), corresponded to the epigenetic factors Hdac1 , Mbd2 , Mta2 (components of Mi-2/nucleosomal remodeling and deacetylase (NuRD) complexes) and Smarca4 , the glycosylation genes Ost4 , Ostc , Stt3a , Dpm1 and Dpm3 , the vesicle trafficking genes Arf4 and Preb , and the NF-kB signaling gene Nfkbia ( Figures 1C, D and Supplementary Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation

et al. 2023

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IntroductionThe differentiation of B cells into antibody-secreting plasma cells depends on cell division-coupled, epigenetic and other cellular processes that are incompletely understood.MethodsWe have developed a CRISPR/Cas9-based screen that models an early stage of T cell-dependent plasma cell differentiation and measures B cell survival or proliferation versus the formation of CD138+ plasmablasts. Here, we refined and extended this screen to more than 500 candidate genes that are highly expressed in plasma cells.ResultsAmong known genes whose deletion preferentially or mostly affected plasmablast formation were the transcription factors Prdm1 (BLIMP1), Irf4 and Pou2af1 (OBF-1), and the Ern1 gene encoding IRE1a, while deletion of XBP1, the transcriptional master regulator that specifies the expansion of the secretory program in plasma cells, had no effect. Defective plasmablast formation caused by Ern1 deletion could not be rescued by the active, spliced form of XBP1 whose processing is dependent on and downstream of IRE1a, suggesting that in early plasma cell differentiation IRE1a acts independently of XBP1. Moreover, we newly identified several genes involved in NF-kB signaling (Nfkbia), vesicle trafficking (Arf4, Preb) and epigenetic regulators that form part of the NuRD complex (Hdac1, Mta2, Mbd2) to be required for plasmablast formation. Deletion of ARF4, a small GTPase required for COPI vesicle formation, impaired plasmablast formation and blocked antibody secretion. After Hdac1 deletion plasmablast differentiation was consistently reduced by about 50%, while deletion of the closely related Hdac2 gene had no effect. Hdac1 knock-out led to strongly perturbed protein expression of antagonistic transcription factors that govern plasma cell versus B cell identity (by decreasing IRF4 and BLIMP1 and increasing BACH2 and PAX5).DiscussionTaken together, our results highlight specific and non-redundant roles for Ern1, Arf4 and Hdac1 in the early steps of plasma cell differentiation.

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Section: Resultsmentioning

confidence: 99%

A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation

et al. 2023

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“…In plasma cells, IL‐6 can trigger the expression of pim‐2, resulting in a pim‐2‐dependent anti‐apoptotic effect on malignant plasma cells. This also implies a role for pim‐2 in the malignant proliferation of myeloma cells 109 . Stimulated with BLyS (B‐lymphocyte stimulator) pim‐2‐deficient B cells were protected from death, but this protection was completely nullified when treated with rapamycin (an mTOR inhibitor) 110 .…”

Section: Pim Kinase and Immune Modulationmentioning

confidence: 99%

“…The most common adverse event related to pim447 was thrombocytopenia, which accounted for 76.9% of the patients with both anemia and leukopenia (53.8%). 37,71 SGI-1776 and AZD1208 are potent ATP-competitive inhibitors and are in phase 1 clinical trials for the treatment of refractory prostate cancer, RR NHL patients, 72,79 and recurrent or refractory acute myeloid leukemia (AML) patients, 73 respectively. SGI-1776 therapy contributes to apoptosis in myeloma patients with primary CD138 + cells <10%; however, a 70% reduction in DNA synthesis was observed at 3 μM in U266 cells.…”

Section: Single-agent Therapy In MMmentioning

confidence: 99%

“…A study conducted to determine the difference between the maximum tolerated dose (MTD = 300 mg) and recommended expanded dose (250 mg) of pim447 in Japanese relapsed/refractory MM patients (NCT02160951) revealed that among all the patients, the ORR was 15.4% with a disease control rate and clinical benefit of 69.2% and 23.1%, respectively. The most common adverse event related to pim447 was thrombocytopenia, which accounted for 76.9% of the patients with both anemia and leukopenia (53.8%) 37,71 …”

Section: Clinical Efficacy Of Pim Kinase Inhibitors In MMmentioning

confidence: 99%

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An overview of pim kinase as a target in multiple myeloma

et al. 2023

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Multiple myeloma (MM) is the second common hematologic malignancy manifesting as a clonal proliferation of plasma cells in the bone marrow. In recent years, high expression and activity of pim kinase have been found to be associated with both the progression and prognosis of a significant proportion of malignant diseases. Therefore, pim kinase has become a potential therapeutic target in the treatment of MM and some pim kinase inhibitors have demonstrated good efficacy in clinical trials. Based on nearly the entire literature searched from PubMed in the field of pim kinase in MM, the paper concluded how pim kinase got involved in the proliferation of myeloma cells, the progression of bone disease infiltration, and even in the regulation of the immune microenvironment. Next as a very promising drug, the effectiveness of pim kinase inhibitors as single agents or in combination with other drugs in the treatment of MM was also summarized. Our analysis will guide the clinical use of pim kinase inhibitors for managing tumor load and bone disease in MM patients.

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“…PIM2 is highly expressed in malignancies, such as lymphoma and multiple myeloma [ 9 ]. PIM2 functions similarly to PIM1, which seals Bad-induced apoptosis by phosphorylating Bad protein [ 10 ]. PIM2 can also activate the survival pathways of cells by increasing IκB kinase activity and activating the NF-κB signaling pathway to promote the survival of cells [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Role and mechanism of PIM family in the immune microenvironment of diffuse large B cell lymphoma

et al. 2023

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Background Diffuse large B cell lymphoma (DLBCL) is a more common non-Hodgkin lymphoma (NHL). This study aims to explore the prognostic value of PIM kinase family in DLBCL and its relationship with the immune microenvironment, to provide a certain reference for the prognosis and treatment of DLBCL. Methods The prognostic value of PIM kinase family in DLBCL from the data set GSE10846 was verified through survival analysis and cox regression analysis. Mutations in PIM kinase family and its relationship with immune cell infiltration were explored with online cBioPortal, TIMER database, and single-gene GSEA analysis. Finally, the expression of PIM kinase family in tissues from DLBCL clinical samples was validated through immunohistochemical staining. Results The proteins of PIM kinase family were highly expressed in DLBCL patients, which are good prognostic factors for DLBCL patients. Then, PIM1-3 proteins were positively correlated with the immune infiltration of B cells, whose types of mutations also showed different degrees of correlation with B cells. PIM kinase family proteins also showed a high correlation with PDL1. In addition, PIM kinase family was also associated with the commonly mutated genes in DLBCL, such as MYD88, MYC, and BTK. Conclusion PIM kinase family may be a potential therapeutic target for DLBCL patients.

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

Cited by 8 publications

References 57 publications

A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation

A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation

An overview of pim kinase as a target in multiple myeloma

Role and mechanism of PIM family in the immune microenvironment of diffuse large B cell lymphoma

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