The BLM helicase is a new therapeutic target in multiple myeloma involved in replication stress survival and drug resistance

Sara Ovejero, Elena Viziteu, Laure Dutrieux, Julie Devin, Yea-Lih Lin, Elina Alaterre, Michel Jourdan, Jihane Basbous, Guilhem Requirand, Nicolas Robert, Hugues de Boussac, Anja Seckinger, Dirk Hose, Laure Vincent, Charles Herbaux, Angelos Constantinou, Philippe Pasero, Jérôme Moreaux

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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.

Originele taal-2English
TijdschriftFrontiers in Immunology
StatusPublished - 9 dec 2022

Bibliografische nota

Funding Information:
The JM research group was supported by grants from INCA PLBIO18-362PIT-MM and PLBIO19 FATidique, ANR (TIE-Skip; 2017-CE15-0024-01), ANR-18-CE15-0010-01 PLASMADIFF-3D, SIRIC Montpellier Cancer (INCa_Inserm_D-GOS_12553), Carnot FINDMED, Institut Carnot CALYM, Labex EpiGenMed, FFRMG (AAP-FFRMG-2021), INSERM PSCI 2020 Smooth-MM, Labex Epigenmed and Institut Universitaire de France. Work in PP’s lab is supported by grants from INCA, the Ligue Nationale Contre le Cancer (équipe labellisée), and the Fondation MSDAvenir. LD is supported by a grant from Ligue Nationale Contre le Cancer LNCC. Acknowledgments

Funding Information:
The authors thank the imaging facility MRI, member of the national infrastructure France-Bioimaging supported by the French National Research Agency (ANR-10-INBS-04, Investments for the future).

Publisher Copyright:
Copyright © 2022 Ovejero, Viziteu, Dutrieux, Devin, Lin, Alaterre, Jourdan, Basbous, Requirand, Robert, de Boussac, Seckinger, Hose, Vincent, Herbaux, Constantinou, Pasero and Moreaux.

Copyright 2023 Elsevier B.V., All rights reserved.


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