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Leukemia. 2019 Jul 12. doi: 10.1038/s41375-019-0485-x. [Epub ahead of print]

Genetic characterization of ABT-199 sensitivity in human AML.

Author information

1
The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.
2
Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada.
3
Department of Computer Science and Operations Research, Université de Montréal, Montréal, QC, Canada.
4
Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada.
5
Department of Chemistry, Université de Montréal, Montréal, QC, Canada.
6
Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
7
The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada. guy.sauvageau@umontreal.ca.
8
Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada. guy.sauvageau@umontreal.ca.
9
Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada. guy.sauvageau@umontreal.ca.
10
Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada. guy.sauvageau@umontreal.ca.

Abstract

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.

PMID:
31300747
DOI:
10.1038/s41375-019-0485-x

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