2. Academic Validation
  3. Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics

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

  • Nat Commun. 2022 Oct 2;13(1):5789. doi: 10.1038/s41467-022-33461-z.
Cameron S Fraser 1 2 3,  Johan K E Spetz 1 2 3,  Xingping Qin 1 2 3,  Adam Presser 1 2 3,  Jonathan Choiniere 1 2 3,  Chendi Li 4 5,  Stacey Yu 1 2 3,  Frances Blevins 6 7,  Aaron N Hata 4 5,  Jeffrey W Miller 8,  Gary A Bradshaw 3,  Marian Kalocsay 3 9,  Vaishali Sanchorawala 6 7,  Shayna Sarosiek 10 11 12,  Kristopher A Sarosiek 13 14 15
Affiliations

Affiliations

  • 1 John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health, Boston, MA, 02115, USA.
  • 2 Program in Molecular and Integrative Physiological Sciences, Harvard TH Chan School of Public Health, Boston, MA, 02115, USA.
  • 3 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, 02115, USA.
  • 4 Massachusetts General Hospital Cancer Center, Charlestown, MA, 02129, USA.
  • 5 Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
  • 6 Section of Hematology & Medical Oncology, Boston Medical Center, Boston, MA, 02118, USA.
  • 7 Amyloidosis Center, Boston University School of Medicine, Boston, MA, 02118, USA.
  • 8 Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, 02115, USA.
  • 9 Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 10 Section of Hematology & Medical Oncology, Boston Medical Center, Boston, MA, 02118, USA. Shayna_sarosiek@dfci.harvard.edu.
  • 11 Amyloidosis Center, Boston University School of Medicine, Boston, MA, 02118, USA. Shayna_sarosiek@dfci.harvard.edu.
  • 12 Dana-Farber Cancer Institute, Harvard Cancer Center, Boston, 02215, USA. Shayna_sarosiek@dfci.harvard.edu.
  • 13 John B. Little Center for Radiation Sciences, Harvard TH Chan School of Public Health, Boston, MA, 02115, USA. sarosiek@hsph.harvard.edu.
  • 14 Program in Molecular and Integrative Physiological Sciences, Harvard TH Chan School of Public Health, Boston, MA, 02115, USA. sarosiek@hsph.harvard.edu.
  • 15 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, 02115, USA. sarosiek@hsph.harvard.edu.
PMID: 36184661 DOI: 10.1038/s41467-022-33461-z
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.

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