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Background: Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. The constitutive expression of HIF-1α in MM suggests that inhibition of HIF-1α-mediated transcription represents an interesting target in MM.Methods: As p300 is a crucial co-activator of hypoxia-inducible transcription, disrupting the complex HIF-1α/p300 to target HIF activity appears to be an attractive strategy.Results: We reported that chetomin, an inhibitor of HIF-1α/p300 interaction, exhibits antitumour activity in human myeloma cell lines and primary MM cells from patients.Conclusions: Our data suggest that chetomin may be of clinical value in MM and especially for patients characterised by a high EP300/HIF-1α expression and a poor prognosis. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematologic cancer characterized by accumulation of malignant plasma cells in the bone marrow. To date, no definitive cure exists for MM and resistance to current treatments is one of the major challenges of this disease. The DNA helicase BLM, whose depletion or mutation causes the cancer-prone Bloom's syndrome (BS), is a central factor of DNA damage repair by homologous recombination (HR) and genomic stability maintenance. Using independent cohorts of MM patients, we identified that high expression of BLM is associated with a poor outcome with a significant enrichment in replication stress signature. We provide evidence that chemical inhibition of BLM by the small molecule ML216 in HMCLs (human myeloma cell lines) leads to cell cycle arrest and increases apoptosis, likely by accumulation of DNA damage. BLM inhibition synergizes with the alkylating agent melphalan to efficiently inhibit growth and promote cell death in HMCLs. Moreover, ML216 treatment re-sensitizes melphalan-resistant cell lines to this conventional therapeutic agent. Altogether, these data suggest that inhibition of BLM in combination with DNA damaging agents could be of therapeutic interest in the treatment of MM, especially in those patients with high BLM expression and/or resistance to melphalan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ovejero, Viziteu, Dutrieux, Devin, Lin, Alaterre, Jourdan, Basbous, Requirand, Robert, de Boussac, Seckinger, Hose, Vincent, Herbaux, Constantinou, Pasero and Moreaux.)

Plasma cells (PCs) secrete large amounts of antibodies and develop from B cells that have been activated. PCs are rare cells located in the bone marrow or mucosa and ensure humoral immunity. Due to their low frequency and location, the study of PCs is difficult in human. We reported a B to PC in vitro differentiation model using selected combinations of cytokines and activation molecules that allow to reproduce the sequential cell differentiation occurring in vivo. In this in vitro model, memory B cells (MBCs) will differentiate into pre-plasmablasts (prePBs), plasmablasts (PBs), early PCs and finally, into long-lived PCs, with a phenotype close to their counterparts in healthy individuals. We also built an open access bioinformatics tools to analyze the most prominent information from GEP data related to PC differentiation. These resources can be used to study human B to PC differentiation and in the current study, we investigated the gene expression regulation of epigenetic factors during human B to PC differentiation.