Mechanistic elucidation of novel BCL10 mutations for guiding precision therapy for non-Hodgkin’s lymphomas
2Program in Cellular and Molecular Medicine, Boston Children's Hospital
3Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine
B-cell and T-cell -induced NF-kB signaling has a crucial role in regulating the activation, proliferation, and effector functions of lymphocytes in adaptive immune responses. The ternary complex CARMA1-MALT1-BCL10, known as the CBM complex acts downstream of B-cell and T-cell receptors to induce NF-kB signaling in lymphocytes. Mutations, chromosomal translocations, and overexpression of CBM component proteins have been shown to directly lead to non-Hodgkin’s lymphomas.
The ABC-DLBCL lymphoma is the most aggressive form of lymphoid malignancy that harbors frequent mutations that culminate in constitutive activation of the CBM complex and downstream NF-κB pathway. CBM form high order assemblies due to polymerization of BCL10, which is affected by recurrent somatic mutations in ABC-DLBCLs. Through biochemical, structural and functional dissection of these mutations, we find that BCL10 mutations fall into two classes: missense mutations of the CARD domain and truncation of its C-terminal tail. Truncating mutation abrogated a novel motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutation enhanced BCL10 polymerization and stabilize BCL10 filaments. Furthermore, in vitro and in vivo xenograft studies revealed that BCL10 mutant lymphomas are resistant to BTK inhibitors, whereas BCL10 truncating but not missense CARD mutants were hypersensitive to MALT1 protease inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL and further precision can be achieved by tailoring therapy according to specific biochemical effects of distinct mutation classes.