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

被引：264

作者：

Guieze, Romain ^{[1
,2
,3
,4
,5
]}

Liu, Vivian M. ^{[1
,3
]}

Rosebrock, Daniel ^{[2
]}

Jourdain, Alexis A. ^{[2
,3
,6
,7
]}

Hernandez-Sanchez, Maria ^{[1
,8
,9
]}

Zurita, Aina Martinez ^{[2
]}

Sun, Jing ^{[1
,2
]}

Ten Hacken, Elise ^{[1
,2
,3
]}

Baranowski, Kaitlyn ^{[1
]}

Thompson, Philip A. ^{[10
]}

Heo, Jin-Mi ^{[11
]}

Cartun, Zachary ^{[1
]}

Aygun, Ozan ^{[2
]}

Lorgulescu, J. Bryan ^{[1
,3
,12
]}

Zhang, Wandi ^{[1
]}

Notarangelo, Giulia ^{[1
,3
]}

Livitz, Dimitri ^{[2
]}

Li, Shuoiang ^{[2
]}

Davids, Matthew S. ^{[1
,3
,13
]}

Biran, Anat ^{[1
]}

Fernandes, Stacey M. ^{[1
]}

Brown, Jennifer R. ^{[1
,2
,3
,13
]}

Lako, Ana ^{[14
]}

Ciente, Zoe B. ^{[14
]}

Lawlor, Matthew A. ^{[3
,15
]}

Keskin, Derin B. ^{[1
,2
,3
]}

Udeshi, Namrata D. ^{[2
]}

Wierda, William G. ^{[10
]}

Livak, Kenneth J. ^{[1
]}

Letai, Anthony G. ^{[1
,3
,13
]}

Neuberg, Donna ^{[3
,16
]}

Harper, J. Wade ^{[11
]}

Carr, Steven A. ^{[2
]}

Piccioni, Federica ^{[2
]}

Ott, Christopher J. ^{[3
,15
]}

Leshchiner, Ignaty ^{[2
]}

Johannessen, Cory M. ^{[2
]}

Doench, John ^{[2
]}

Mootha, Vamsi K. ^{[2
,3
,6
,7
]}

Getz, Gad ^{[2
,3
,15
]}

Wu, Catherine J. ^{[1
,2
,3
,13
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana Bldg,Room DA-520, Boston, MA 02215 USA

[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[3] Harvard Med Sch, Boston, MA 02215 USA

[4] CHU Clermont Ferrand, F-63000 Clermont Ferrand, France

[5] Univ Clermont Auvergne, EA7453 CHELTER, F-63000 Clermont Ferrand, France

[6] Howard Hughes Med Inst, Boston, MA 02114 USA

[7] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[8] Univ Salamanca, Inst Invest Biomed Salamanca, Ctr Invest Canc IBMCC, Salamanca 37007, Spain

[9] Hosp Univ Salamanca, Serv Hematol, Salamanca 37007, Spain

[10] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77054 USA

[11] Harvard Med Sch, Dept Cell Biol, Boston, MA 02215 USA

[12] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA

[13] Brigham & Womens Hosp, Dept Med, Boston, MA 02215 USA

[14] Dana Farber Canc Inst, Ctr Immunooncol, Boston, MA 02215 USA

[15] Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02214 USA

[16] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

来源：

CANCER CELL | 2019年 / 36卷 / 04期

基金：

瑞士国家科学基金会;

关键词：

READ ALIGNMENT; MUTATIONS; EXPRESSION; GENE; ABT-737; LEUKEMIA; CELLS; VENETOCLAX; GENERATION; EVOLUTION;

D O I：

10.1016/j.ccell.2019.08.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：369 / +

页数：29

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