Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies

Romain Guièze; Vivian M. Liu; Daniel Rosebrock; Alexis A. Jourdain; María Hernández-Sánchez; Aina Martinez Zurita; Jing Sun; Elisa Ten Hacken; Kaitlyn Baranowski; Philip A. Thompson; Jin Mi Heo; Zachary Cartun; Ozan Aygün; J. Bryan Iorgulescu; Wandi Zhang; Giulia Notarangelo; Dimitri Livitz; Shuqiang Li; Matthew S. Davids; Anat Biran; Stacey M. Fernandes; Jennifer R. Brown; Ana Lako; Zoe B. Ciantra; Matthew A. Lawlor; Derin B. Keskin; Namrata D. Udeshi; William G. Wierda; Kenneth J. Livak; Anthony G. Letai; Donna Neuberg; J. Wade Harper; Steven A. Carr; Federica Piccioni; Christopher J. Ott; Ignaty Leshchiner; Cory M. Johannessen; John Doench; Vamsi K. Mootha; Gad Getz; Catherine J. Wu

doi:10.1016/j.ccell.2019.08.005

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies

Romain Guièze, Vivian M. Liu, Daniel Rosebrock, Alexis A. Jourdain, María Hernández-Sánchez, Aina Martinez Zurita, Jing Sun, Elisa Ten Hacken, Kaitlyn Baranowski, Philip A. Thompson, Jin Mi Heo, Zachary Cartun, Ozan Aygün, J. Bryan Iorgulescu, Wandi Zhang, Giulia Notarangelo, Dimitri Livitz, Shuqiang Li, Matthew S. Davids, Anat BiranStacey M. Fernandes, Jennifer R. Brown, Ana Lako, Zoe B. Ciantra, Matthew A. Lawlor, Derin B. Keskin, Namrata D. Udeshi, William G. Wierda, Kenneth J. Livak, Anthony G. Letai, Donna Neuberg, J. Wade Harper, Steven A. Carr, Federica Piccioni, Christopher J. Ott, Ignaty Leshchiner, Cory M. Johannessen, John Doench, Vamsi K. Mootha, Gad Getz, Catherine J. Wu

Leukemia

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

210 Scopus citations

Abstract

Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.

Original language	English (US)
Pages (from-to)	369-384.e13
Journal	Cancer cell
Volume	36
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2019.08.005
State	Published - Oct 14 2019

Keywords

AMPK
BCL-2
CRISPR/Cas9
chronic lymphocytic leukemia
clonal evolution
drug resistance
genome-wide screen
metabolism
mitochondrion
venetoclax

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

MD Anderson CCSG core facilities

Tissue Biospecimen and Pathology Resource
Clinical Trials Office

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10.1016/j.ccell.2019.08.005

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Guièze, R., Liu, V. M., Rosebrock, D., Jourdain, A. A., Hernández-Sánchez, M., Martinez Zurita, A., Sun, J., Ten Hacken, E., Baranowski, K., Thompson, P. A., Heo, J. M., Cartun, Z., Aygün, O., Iorgulescu, J. B., Zhang, W., Notarangelo, G., Livitz, D., Li, S., Davids, M. S., ... Wu, C. J. (2019). Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies. Cancer cell, 36(4), 369-384.e13. https://doi.org/10.1016/j.ccell.2019.08.005

Guièze, R, Liu, VM, Rosebrock, D, Jourdain, AA, Hernández-Sánchez, M, Martinez Zurita, A, Sun, J, Ten Hacken, E, Baranowski, K, Thompson, PA, Heo, JM, Cartun, Z, Aygün, O, Iorgulescu, JB, Zhang, W, Notarangelo, G, Livitz, D, Li, S, Davids, MS, Biran, A, Fernandes, SM, Brown, JR, Lako, A, Ciantra, ZB, Lawlor, MA, Keskin, DB, Udeshi, ND, Wierda, WG, Livak, KJ, Letai, AG, Neuberg, D, Harper, JW, Carr, SA, Piccioni, F, Ott, CJ, Leshchiner, I, Johannessen, CM, Doench, J, Mootha, VK, Getz, G & Wu, CJ 2019, 'Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies', Cancer cell, vol. 36, no. 4, pp. 369-384.e13. https://doi.org/10.1016/j.ccell.2019.08.005

@article{8be74ad3497d42408e454a1c26dbb5d1,

title = "Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies",

abstract = "Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.",

keywords = "AMPK, BCL-2, CRISPR/Cas9, chronic lymphocytic leukemia, clonal evolution, drug resistance, genome-wide screen, metabolism, mitochondrion, venetoclax",

author = "Romain Gui{\`e}ze and Liu, {Vivian M.} and Daniel Rosebrock and Jourdain, {Alexis A.} and Mar{\'i}a Hern{\'a}ndez-S{\'a}nchez and {Martinez Zurita}, Aina and Jing Sun and {Ten Hacken}, Elisa and Kaitlyn Baranowski and Thompson, {Philip A.} and Heo, {Jin Mi} and Zachary Cartun and Ozan Ayg{\"u}n and Iorgulescu, {J. Bryan} and Wandi Zhang and Giulia Notarangelo and Dimitri Livitz and Shuqiang Li and Davids, {Matthew S.} and Anat Biran and Fernandes, {Stacey M.} and Brown, {Jennifer R.} and Ana Lako and Ciantra, {Zoe B.} and Lawlor, {Matthew A.} and Keskin, {Derin B.} and Udeshi, {Namrata D.} and Wierda, {William G.} and Livak, {Kenneth J.} and Letai, {Anthony G.} and Donna Neuberg and Harper, {J. Wade} and Carr, {Steven A.} and Federica Piccioni and Ott, {Christopher J.} and Ignaty Leshchiner and Johannessen, {Cory M.} and John Doench and Mootha, {Vamsi K.} and Gad Getz and Wu, {Catherine J.}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = oct,

day = "14",

doi = "10.1016/j.ccell.2019.08.005",

language = "English (US)",

volume = "36",

pages = "369--384.e13",

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T1 - Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies

AU - Guièze, Romain

AU - Liu, Vivian M.

AU - Rosebrock, Daniel

AU - Jourdain, Alexis A.

AU - Hernández-Sánchez, María

AU - Martinez Zurita, Aina

AU - Sun, Jing

AU - Ten Hacken, Elisa

AU - Baranowski, Kaitlyn

AU - Thompson, Philip A.

AU - Heo, Jin Mi

AU - Cartun, Zachary

AU - Aygün, Ozan

AU - Iorgulescu, J. Bryan

AU - Zhang, Wandi

AU - Notarangelo, Giulia

AU - Livitz, Dimitri

AU - Li, Shuqiang

AU - Davids, Matthew S.

AU - Biran, Anat

AU - Fernandes, Stacey M.

AU - Brown, Jennifer R.

AU - Lako, Ana

AU - Ciantra, Zoe B.

AU - Lawlor, Matthew A.

AU - Keskin, Derin B.

AU - Udeshi, Namrata D.

AU - Wierda, William G.

AU - Livak, Kenneth J.

AU - Letai, Anthony G.

AU - Neuberg, Donna

AU - Harper, J. Wade

AU - Carr, Steven A.

AU - Piccioni, Federica

AU - Ott, Christopher J.

AU - Leshchiner, Ignaty

AU - Johannessen, Cory M.

AU - Doench, John

AU - Mootha, Vamsi K.

AU - Getz, Gad

AU - Wu, Catherine J.

PY - 2019/10/14

Y1 - 2019/10/14

N2 - Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.

AB - Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.

KW - AMPK

KW - BCL-2

KW - CRISPR/Cas9

KW - chronic lymphocytic leukemia

KW - clonal evolution

KW - drug resistance

KW - genome-wide screen

KW - metabolism

KW - mitochondrion

KW - venetoclax

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DO - 10.1016/j.ccell.2019.08.005

M3 - Article

C2 - 31543463

AN - SCOPUS:85072936111

SN - 1535-6108

VL - 36

SP - 369-384.e13

JO - Cancer cell

JF - Cancer cell

IS - 4

ER -

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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