Genetic characterization of ABT-199 sensitivity in human AML

被引:81
作者
Bisaillon, Richard [1 ]
Moison, Celine [1 ]
Thiollier, Clarisse [1 ]
Krosl, Jana [1 ]
Bordeleau, Marie-Eve [1 ]
Lehnertz, Bernhard [1 ]
Lavallee, Vincent-Philippe [1 ,2 ]
MacRae, Tara [1 ]
Mayotte, Nadine [1 ]
Labelle, Caroline [1 ,3 ]
Boucher, Genevieve [1 ]
Spinella, Jean-Francois [1 ]
Boivin, Isabel [1 ]
D'Angelo, Giovanni [4 ]
Lavallee, Sylvie [4 ]
Marinier, Anne [1 ,5 ]
Lemieux, Sebastien [1 ,3 ]
Hebert, Josee [1 ,2 ,4 ,6 ]
Sauvageau, Guy [1 ,2 ,4 ,6 ]
机构
[1] Univ Montreal, Leucegene Project Inst Res Immunol & Canc, Montreal, PQ, Canada
[2] Maisonneuve Rosemont Hosp, Div Hematol, Montreal, PQ, Canada
[3] Univ Montreal, Dept Comp Sci & Operat Res, Montreal, PQ, Canada
[4] Maisonneuve Rosemont Hosp, Quebec Leukemia Cell Bank, Montreal, PQ, Canada
[5] Univ Montreal, Dept Chem, Montreal, PQ, Canada
[6] Univ Montreal, Fac Med, Dept Med, Montreal, PQ, Canada
关键词
ACUTE MYELOID-LEUKEMIA; MUTATIONS; BCL-2; VENETOCLAX; APOPTOSIS; CLASSIFICATION; IDENTIFICATION; EXPRESSION; INHIBITOR; GROWTH;
D O I
10.1038/s41375-019-0485-x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Acute myeloid leukemias (AML) with mutations in the NPM1 gene (NPM1c+) represent a large AML subgroup with varying response to conventional treatment, highlighting the need to develop targeted therapeutic strategies for this disease. We screened a library of clinical drugs on a cohort of primary human AML specimens and identified the BCL2 inhibitor ABT-199 as a selective agent against NPM1c+ AML. Mutational analysis of ABT-199-sensitive and -resistant specimens identified mutations in NPM1, RAD21, and IDH1/IDH2 as predictors of ABT-199 sensitivity. Comparative transcriptome analysis further uncovered BCL2A1 as a potential mediator of ABT-199 resistance in AML. In line with our observation that RAD21 mutation confers sensitivity to ABT-199, we provide functional evidence that reducing RAD21 levels can sensitize AML cells to BCL2 inhibition. Moreover, we demonstrate that ABT-199 is able to produce selective anti-AML activity in vivo toward AML with mutations associated with compound sensitivity in PDX models. Overall, this study delineates the contribution of several genetic events to the response to ABT-199 and provides a rationale for the development of targeted therapies for NPM1c+ AML.
引用
收藏
页码:63 / 74
页数:12
相关论文
共 32 条
[1]   The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia [J].
Arber, Daniel A. ;
Orazi, Attilio ;
Hasserjian, Robert ;
Thiele, Jurgen ;
Borowitz, Michael J. ;
Le Beau, Michelle M. ;
Bloomfield, Clara D. ;
Cazzola, Mario ;
Vardiman, James W. .
BLOOD, 2016, 127 (20) :2391-2405
[2]  
Atienza JM, 2005, MOL CANCER THER, V4, P361
[3]   Combined venetoclax and alvocidib in acute myeloid leukemia [J].
Bogenberger, James ;
Whatcott, Clifford ;
Hansen, Nanna ;
Delman, Devora ;
Shi, Chang-Xin ;
Kim, Wontak ;
Haws, Hillary ;
Soh, Katherine ;
Lee, Ye Sol ;
Peterson, Peter ;
Siddiqui-Jain, Adam ;
Weitman, Steven ;
Stewart, Keith ;
Bearss, David ;
Mesa, Ruben ;
Warner, Steven ;
Tibes, Raoul .
ONCOTARGET, 2017, 8 (63) :107206-107222
[4]   Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo [J].
Carrington, Emma M. ;
Zhan, Yifan ;
Brady, Jamie L. ;
Zhang, Jian-Guo ;
Sutherland, Robyn M. ;
Anstee, Natasha S. ;
Schenk, Robyn L. ;
Vikstrom, Ingela B. ;
Delconte, Rebecca B. ;
Segal, David ;
Huntington, Nicholas D. ;
Bouillet, Philippe ;
Tarlinton, David M. ;
Huang, David C. S. ;
Strasser, Andreas ;
Cory, Suzanne ;
Herold, Marco J. ;
Lew, Andrew M. .
CELL DEATH AND DIFFERENTIATION, 2017, 24 (05) :878-888
[5]   Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia [J].
Chan, Steven M. ;
Thomas, Daniel ;
Corces-Zimmerman, M. Ryan ;
Xavy, Seethu ;
Rastogi, Suchita ;
Hong, Wan-Jen ;
Zhao, Feifei ;
Medeiros, Bruno C. ;
Tyvoll, David A. ;
Majeti, Ravindra .
NATURE MEDICINE, 2015, 21 (02) :178-184
[6]  
de Araujo A, 2018, J MED CHEM
[7]   Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study [J].
DiNardo, Courtney L. ;
Pratz, Keith W. ;
Letai, Anthony ;
Jonas, Brian A. ;
Wei, Andrew H. ;
Thirman, Michael ;
Arellano, Martha ;
Frattini, Mark G. ;
Kantarjian, Hagop ;
Popovic, Relja ;
Chyla, Brenda ;
Xu, Tu ;
Dunbar, Martin ;
Agarwal, Suresh K. ;
Humerickhouse, Rod ;
Mabry, Mack ;
Potluri, Jalaja ;
Konopleva, Marina ;
Pollyea, Daniel A. .
LANCET ONCOLOGY, 2018, 19 (02) :216-228
[8]   Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel [J].
Doehner, Hartmut ;
Estey, Elihu ;
Grimwade, David ;
Amadori, Sergio ;
Appelbaum, Frederick R. ;
Buechner, Thomas ;
Dombret, Herve ;
Ebert, Benjamin L. ;
Fenaux, Pierre ;
Larson, Richard A. ;
Levine, Ross L. ;
Lo-Coco, Francesco ;
Naoe, Tomoki ;
Niederwieser, Dietger ;
Ossenkoppele, Gert J. ;
Sanz, Miguel ;
Sierra, Jorge ;
Tallman, Martin S. ;
Tien, Hwei-Fang ;
Wei, Andrew H. ;
Lowenberg, Bob ;
Bloomfield, Clara D. .
BLOOD, 2017, 129 (04) :424-447
[9]  
Esteve-Arenys A, 2018, ONCOGENE
[10]   Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML):: biologic and clinical features [J].
Falini, Brunangelo ;
Nicoletti, Ildo ;
Martelli, Massimo F. ;
Mecucci, Cristina .
BLOOD, 2007, 109 (03) :874-885