Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies

被引：15

作者：

Chong, Stephen Jun Fei ^{[1
]}

Zhu, Fen ^{[1
]}

Dashevsky, Olga ^{[1
]}

Mizuno, Rin ^{[1
]}

Lai, Jolin X. H. ^{[2
]}

Hackett, Liam ^{[1
]}

Ryan, Christine E. ^{[1
]}

Collins, Mary C. ^{[1
]}

Iorgulescu, J. Bryan ^{[1
,3
,9
]}

Guieze, Romain ^{[1
]}

Penailillo, Johany ^{[1
,3
]}

Carrasco, Ruben ^{[1
,3
]}

Hwang, Yeonjoo C. ^{[4
]}

Munoz, Denise P. ^{[4
]}

Bouhaddou, Mehdi ^{[5
]}

Lim, Yaw Chyn ^{[6
]}

Wu, Catherine J. ^{[1
]}

Allan, John N. ^{[7
]}

Furman, Richard R.

Goh, Boon Cher ^{[6
]}

Pervaiz, Shazib ^{[2
]}

Coppe, Jean-Philippe ^{[4
]}

Mitsiades, Constantine S. ^{[1
]}

Davids, Matthew S. ^{[1
,8
]}

机构：

[1] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[2] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore, Singapore

[3] Brigham & Womens Hosp, Dept Pathol, Boston, MA USA

[4] UCSF, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA

[5] UCLA, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA

[6] Natl Univ Singapore, Canc Sci Inst, Singapore, Singapore

[7] Weill Cornell Med, Div Hematol & Med Oncol, New York, NY USA

[8] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Div Pathol & Lab Med, Mol Diagnost Lab, Houston, TX USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 22期

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; PHOSPHATASE; 2A; PROAPOPTOTIC FUNCTION; DOWN-REGULATION; PHOSPHORYLATION; APOPTOSIS; MCL-1; ACTIVATION; INHIBITION; ABT-199;

D O I：

10.1172/JCI170169

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.

引用

页数：21

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