Genetic characterization of ABT-199 sensitivity in human AML

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 hum...

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Bibliographic Details
Published in:Leukemia 2020-01, Vol.34 (1), p.63-74
Main Authors: Bisaillon, Richard, Moison, Céline, Thiollier, Clarisse, Krosl, Jana, Bordeleau, Marie-Eve, Lehnertz, Bernhard, Lavallée, Vincent-Philippe, MacRae, Tara, Mayotte, Nadine, Labelle, Caroline, Boucher, Geneviève, Spinella, Jean-François, Boivin, Isabel, D'Angelo, Giovanni, Lavallée, Sylvie, Marinier, Anne, Lemieux, Sébastien, Hébert, Josée, Sauvageau, Guy
Format: Article
Language:English
Subjects:
Antimitotic agents
Antineoplastic agents
Comparative analysis
Gene expression
Genetic aspects
Genetic research
Health aspects
Leukemia
Medical screening
Mutation
Sensitivity analysis
Subgroups
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Summary: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.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-019-0485-x