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

Stephen Jun Fei Chong; Fen Zhu; Olga Dashevsky; Rin Mizuno; Jolin X.H. Lai; Liam Hackett; Christine E. Ryan; Mary C. Collins; J. Bryan Iorgulescu; Romain Guièze; Johany Penailillo; Ruben Carrasco; Yeonjoo C. Hwang; Denise P. Muñoz; Mehdi Bouhaddou; Yaw Chyn Lim; Catherine J. Wu; John N. Allan; Richard R. Furman; Boon Cher Goh; Shazib Pervaiz; Jean Philippe Coppé; Constantine S. Mitsiades; Matthew S. Davids

doi:10.1172/JCI170169

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

Stephen Jun Fei Chong, Fen Zhu, Olga Dashevsky, Rin Mizuno, Jolin X.H. Lai, Liam Hackett, Christine E. Ryan, Mary C. Collins, J. Bryan Iorgulescu, Romain Guièze, Johany Penailillo, Ruben Carrasco, Yeonjoo C. Hwang, Denise P. Muñoz, Mehdi Bouhaddou, Yaw Chyn Lim, Catherine J. Wu, John N. Allan, Richard R. Furman, Boon Cher GohShazib Pervaiz, Jean Philippe Coppé, Constantine S. Mitsiades, Matthew S. Davids

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e170169
Journal	Journal of Clinical Investigation
Volume	133
Issue number	22
DOIs	https://doi.org/10.1172/JCI170169
State	Published - Sep 26 2023
Externally published	Yes

Keywords

Apoptosis survival pathways
Hematology
Oncology
Phosphoprotein phosphatases
Protein kinases

ASJC Scopus subject areas

General Medicine

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10.1172/JCI170169

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Chong, S. J. F., Zhu, F., Dashevsky, O., Mizuno, R., Lai, J. X. H., Hackett, L., Ryan, C. E., Collins, M. C., Iorgulescu, J. B., Guièze, R., Penailillo, J., Carrasco, R., Hwang, Y. C., Muñoz, D. P., Bouhaddou, M., Lim, Y. C., Wu, C. J., Allan, J. N., Furman, R. R., ... Davids, M. S. (2023). Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies. Journal of Clinical Investigation, 133(22), Article e170169. https://doi.org/10.1172/JCI170169

Chong, SJF, Zhu, F, Dashevsky, O, Mizuno, R, Lai, JXH, Hackett, L, Ryan, CE, Collins, MC, Iorgulescu, JB, Guièze, R, Penailillo, J, Carrasco, R, Hwang, YC, Muñoz, DP, Bouhaddou, M, Lim, YC, Wu, CJ, Allan, JN, Furman, RR, Goh, BC, Pervaiz, S, Coppé, JP, Mitsiades, CS & Davids, MS 2023, 'Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies', Journal of Clinical Investigation, vol. 133, no. 22, e170169. https://doi.org/10.1172/JCI170169

@article{ffbcbedd623c41d7a06504425284fe6b,

title = "Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies",

abstract = "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.",

keywords = "Apoptosis survival pathways, Hematology, Oncology, Phosphoprotein phosphatases, Protein kinases",

author = "Chong, {Stephen Jun Fei} and Fen Zhu and Olga Dashevsky and Rin Mizuno and Lai, {Jolin X.H.} and Liam Hackett and Ryan, {Christine E.} and Collins, {Mary C.} and Iorgulescu, {J. Bryan} and Romain Gui{\`e}ze and Johany Penailillo and Ruben Carrasco and Hwang, {Yeonjoo C.} and Mu{\~n}oz, {Denise P.} and Mehdi Bouhaddou and Lim, {Yaw Chyn} and Wu, {Catherine J.} and Allan, {John N.} and Furman, {Richard R.} and Goh, {Boon Cher} and Shazib Pervaiz and Copp{\'e}, {Jean Philippe} and Mitsiades, {Constantine S.} and Davids, {Matthew S.}",

note = "Publisher Copyright: Copyright: {\textcopyright} 2023, Chong et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.",

year = "2023",

month = sep,

day = "26",

doi = "10.1172/JCI170169",

language = "English (US)",

volume = "133",

journal = "Journal of Clinical Investigation",

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T1 - Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies

AU - Chong, Stephen Jun Fei

AU - Zhu, Fen

AU - Dashevsky, Olga

AU - Mizuno, Rin

AU - Lai, Jolin X.H.

AU - Hackett, Liam

AU - Ryan, Christine E.

AU - Collins, Mary C.

AU - Iorgulescu, J. Bryan

AU - Guièze, Romain

AU - Penailillo, Johany

AU - Carrasco, Ruben

AU - Hwang, Yeonjoo C.

AU - Muñoz, Denise P.

AU - Bouhaddou, Mehdi

AU - Lim, Yaw Chyn

AU - Wu, Catherine J.

AU - Allan, John N.

AU - Furman, Richard R.

AU - Goh, Boon Cher

AU - Pervaiz, Shazib

AU - Coppé, Jean Philippe

AU - Mitsiades, Constantine S.

AU - Davids, Matthew S.

PY - 2023/9/26

Y1 - 2023/9/26

N2 - 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.

AB - 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.

KW - Apoptosis survival pathways

KW - Hematology

KW - Oncology

KW - Phosphoprotein phosphatases

KW - Protein kinases

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U2 - 10.1172/JCI170169

DO - 10.1172/JCI170169

M3 - Article

C2 - 37751299

AN - SCOPUS:85177103551

SN - 0021-9738

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 22

M1 - e170169

ER -

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

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