MCL-1 dependency as a novel vulnerability for aggressive B cell lymphomas
Michelle Wang, Tao Li, Yuan Ren, Bijal Shah, Tint Lwin, Jing Gao, Kenneth H. Shain, Wei Zhang, Xiaohong Zhao, Jianguo Tao
Abstract
Mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL) are aggressive hematologic malignancies characterized by the accumulation of lymphoid cells defective in cell apoptosis biology and function 1 . The anti-apoptotic B cell lymphoma 2 (BCL-2) family proteins are pivotal regulators of the mitochondrial apoptotic pathway and genetic aberrations in these genes are associated with lymphomagenesis and chemotherapeutic resistance. These anti-apoptotic proteins, most notably BCL-2 and myeloid cell leukemia 1 (MCL-1), promote the survival of lymphoma cells by counteracting the activity of pro-apoptotic proteins such as BCL-2-like protein 11 (BCL2L11, also known as BIM) 2-4 . Pharmacological targeting of BCL-2 is highly effective in certain B cell lymphomas, but de novo and acquired resistance to BCL-2 inhibitor monotherapy often develop, especially in aggressive B cell lymphomas. Moreover, the other major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are demonstrated to be the main determinants of resistance to venetoclax 5 . Additionally, MCL-1 is recurrently highly expressed in various kinds of non-Hodgkin's B cell lymphomas 6 . Collectively, these data support the hypothesis that MCL-1 plays a central role in B cell lymphoma progression and drug resistance. Pharmacologically targeting MCL-1, therefore, represents an attractive strategy to combat these lymphomas. To this end, there is a great need to develop and apply selective small-molecule MCL-1 inhibitors as part of a first-line