Large-scale dependency and drug screens to characterize the therapeutic vulnerabilities of multiple myeloma with 1q+

The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

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Publication Details

Journal
Blood
Published
2025-03-12
DOI
https://doi.org/10.1182/blood.2024025102
Citations
3
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
Field-Weighted Citation Impact
5.31
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Large-scale dependency and drug screens to characterize the therapeutic vulnerabilities of multiple myeloma with 1q+

Carolyn Brandt, Gad A. Getz, Alexander Yaw Fui Chung, Jean-Baptiste Alberge et al.
3 citations
Blood
Multiple Myeloma Research and Treatments
5.31
article

Large-scale dependency and drug screens to characterize the therapeutic vulnerabilities of multiple myeloma with 1q+

Carolyn Brandt, Gad A. Getz, Alexander Yaw Fui Chung, Jean-Baptiste Alberge, Harvey G. Roweth, Brianna Berrios, Liam Hackett, Nang Kham Su, Elizabeth D. Lightbody, Irene M. Ghobrial, Mairéad Reidy, Michelle P. Aranha, Salomon Manier, Junko Tsuji, Ankit K. Dutta, Stephen Jun Fei Chong, Matthew Steven Davids, Nicholas J. Haradhvala, Daniel Heilpern-Mallory, Romanos Sklavenitis‐Pistofidis, Jeremy Zhang, Saveliy Belkin, Patricia T. Greipp, Ting Wu, Maria Papaioannou, Ryan A. Knudson, Daisy Huyng
article en
3 citations

Abstract

The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

BloodVol. 146(1)
Broad Institute (US), Brigham and Women's Hospital (US), Mayo Clinic (US), Harvard University (US), Inserm (FR), National University of Singapore (SG), Aristotle University of Thessaloniki (GR), AHEPA University Hospital (GR), Centre Hospitalier Universitaire de Lille (FR), Massachusetts General Hospital (US), Centre de Recherche Jean Pierre Aubert (FR), National University Cancer Institute, Singapore (SG), Dana-Farber Cancer Institute (US), Mayo Clinic in Arizona (US), National Cancer Centre Singapore (SG), Massachusetts Institute of Technology (US)
Good health and well-being
Openalex Percentile: Top 5%
Multiple Myeloma Research and Treatments
5.31
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