Publication — IRIC

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 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.

Publication date
July 12, 2019
Principal Investigators
Bisaillon R, Moison C, Thiollier C, Krosl J, Bordeleau ME, Lehnertz B, Lavallée VP, MacRae T, Mayotte N, Labelle C, Boucher G, Spinella JF, Boivin I, D'Angelo G, Lavallée S, Marinier A, Lemieux S, Hébert J, Sauvageau G
PubMed reference
Leukemia 2019
PubMed ID
31300747
Affiliation
The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.