AUTHOR=Ovejero Sara , Viziteu Elena , Dutrieux Laure , Devin Julie , Lin Yea-Lih , Alaterre Elina , Jourdan Michel , Basbous Jihane , Requirand Guilhem , Robert Nicolas , de Boussac Hugues , Seckinger Anja , Hose Dirk , Vincent Laure , Herbaux Charles , Constantinou Angelos , Pasero Philippe , Moreaux Jérôme TITLE=The BLM helicase is a new therapeutic target in multiple myeloma involved in replication stress survival and drug resistance JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.983181 DOI=10.3389/fimmu.2022.983181 ISSN=1664-3224 ABSTRACT=

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.