Work

MCL-1 dependency as a novel vulnerability for aggressive B cell lymphomas

Year: 2021

Type: article

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 , 3 , 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 lymphoma therapy or upon emergence of tumor resistance characterized by upregulation of MCL-1.

Source: Blood Cancer Journal

DOI: 10.1038/s41408-020-00402-2