Clonal plasma cells in AL amyloidosis are dependent on pro survival BCL-2 family proteins and sensitive to BH3 mimetics

Abstract

Immunoglobulin light chain (AL) amyloidosis is a protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains misfold and accumulate as amyloid fibrils in healthy tissues causing devastating multi-organ dysfunction that is rapidly fatal. Current treatment regimens, which include proteasome inhibitors, alkylating agents, and immunomodulatory agents, were developed for the treatment of the more common plasma cell disease, multiple myeloma, and have limited efficacy in AL amyloidosis as demonstrated by the median survival of 2-3 years. The recent development of novel small-molecule inhibitors of the major pro-survival proteins from the apoptosis-regulating BCL-2 family has created an opportunity to therapeutically target abnormal cell populations, yet identifying the extent of these dependencies and how to target them clinically has thus far been challenging. Using bone marrow-derived plasma cells from 45 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins. Specifically, we find that clonal plasma cells in a majority of patients are highly dependent on the pro-survival protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor as a single agent. In addition, BCL-2 inhibition sensitizes clonal plasma cells to several current standard of care therapies. Our results suggest that BH3 mimetics, when deployed rationally, may be highly effective therapies for AL amyloidosis.