Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics

Cameron S. Fraser, Johan K. E. Spetz, Xingping Qin, Adam Presser, Jonathan Choiniere, Chendi Li, Stacey Yu, Frances Blevins, Aaron N. Hata, Jeffrey W. Miller, Gary A. Bradshaw, Marian Kalocsay, Vaishali Sanchorawala, Shayna Sarosiek () and Kristopher A. Sarosiek ()
Additional contact information
Cameron S. Fraser: John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health
Johan K. E. Spetz: John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health
Xingping Qin: John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health
Adam Presser: John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health
Jonathan Choiniere: John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health
Chendi Li: Massachusetts General Hospital Cancer Center
Stacey Yu: John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health
Frances Blevins: Section of Hematology & Medical Oncology, Boston Medical Center
Aaron N. Hata: Massachusetts General Hospital Cancer Center
Jeffrey W. Miller: Harvard TH Chan School of Public Health
Gary A. Bradshaw: Laboratory of Systems Pharmacology, Harvard Medical School
Marian Kalocsay: Laboratory of Systems Pharmacology, Harvard Medical School
Vaishali Sanchorawala: Section of Hematology & Medical Oncology, Boston Medical Center
Shayna Sarosiek: Section of Hematology & Medical Oncology, Boston Medical Center
Kristopher A. Sarosiek: John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Immunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic light chains by clonal plasma cells. These light chains misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that the clonal plasma cells in AL amyloidosis are highly primed to undergo apoptosis and dependent on pro-survival proteins MCL-1 and BCL-2. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, currently the standard of care for this disease and the related plasma cell disorder multiple myeloma, due to upregulation of pro-apoptotic Noxa and its inhibitory binding to MCL-1. BCL-2 inhibitors sensitize clonal plasma cells to multiple front-line therapies including bortezomib, dexamethasone and lenalidomide. Strikingly, in mice bearing AL amyloidosis cell line xenografts, single agent treatment with the BCL-2 inhibitor ABT-199 (venetoclax) produces deeper remissions than bortezomib and triples median survival. Mass spectrometry-based proteomic analysis reveals rewiring of signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapies. These findings provide a roadmap for the use of BH3 mimetics to exploit endogenous and induced apoptotic vulnerabilities in AL amyloidosis.

Date: 2022
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DOI: 10.1038/s41467-022-33461-z

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