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Acute myeloid leukemia

Genetic characterization of ABT-199 sensitivity in human AML

Leukemia volume 34, pages 63–74 (2020)Cite this article

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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.

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Acknowledgements

We wish to thank Dr. Andrew H. Wei for careful revision of this manuscript and insightful recommendations, Muriel Draoui for project coordination as well as Mélanie Fréchette and Valérie Blouin-Chagnon for their help with animal care and in vivo studies. We acknowledge the contribution of people from the IRIC core facilities (CF): Marianne Arteau and Raphaëlle Lambert of the Genomics CF for RNA sequencing; Jean Duchaine, Dominic Salois, and Sébastien Guiral of the HTS CF for assay optimization and chemical screen supervision; Danièle Gagné and Gaël Dulude of the Cytometry CF for assistance with flow cytometry acquisition and analysis. We also acknowledge the Banque de Cellules Leucémiques du Québec (BCLQ) for providing characterized AML samples of the Leucegene cohort with special thanks to Claude Rondeau. C. Moison was supported by a CIHR fellowship. C. Thiollier was supported by the Cole Foundation. V-P Lavallée was supported by a Cole Foundation fellowship and by a Vanier Canada Graduate Scholarship. C Labelle was supported by the Faculty of Graduate and Postdoctoral Studies (Université de Montréal). J-F Spinella was supported by an Ivado fellowship. This work was in part supported by a CCSRI impact grant no. 701573 to G Sauvageau. The work was also supported by the Government of Canada through Genome Canada and the Ministère de l'économie, de l'innovation et des exportations du Québec through Génome Québec, with supplementary funds from AmorChem (2012 Large-Scale Applied Research Project Competition in Genomics and Personalized Health grant no. 4524); G Sauvageau, J Hébert, A Marinier, and S Lemieux are co- applicants for this grant. G Sauvageau and J Hébert are recipients of research chairs from the Canada Research Chair program and Industrielle-Alliance (Université de Montréal), respectively. The BCLQ is supported by grants from the Cancer Research Network of the Fonds de recherche du Québec-Santé (FRQS).

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Authors and Affiliations

  1. The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada

    Richard Bisaillon, Céline Moison, Clarisse Thiollier, Jana Krosl, Marie-Eve Bordeleau, Bernhard Lehnertz, Vincent-Philippe Lavallée, Tara MacRae, Nadine Mayotte, Caroline Labelle, Geneviève Boucher, Jean-François Spinella, Isabel Boivin, Anne Marinier, Sébastien Lemieux, Josée Hébert & Guy Sauvageau

  2. Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada

    Vincent-Philippe Lavallée, Josée Hébert & Guy Sauvageau

  3. Department of Computer Science and Operations Research, Université de Montréal, Montréal, QC, Canada

    Caroline Labelle & Sébastien Lemieux

  4. Quebec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada

    Giovanni D’Angelo, Sylvie Lavallée, Josée Hébert & Guy Sauvageau

  5. Department of Chemistry, Université de Montréal, Montréal, QC, Canada

    Anne Marinier

  6. Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada

    Josée Hébert & Guy Sauvageau

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  1. Richard Bisaillon
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  2. Céline Moison
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Contributions

Conception and design: RB, CM, CT, JK, BL, V-PL, JH, GS. Development of methodology: RB, CM, CT, JK, BL, V-PL, TM. Acquisition of data (chemical screen, patients, etc.): RB, CM, CT, JK, JH, GDA, SL, TM, IB. Analysis and interpretation of data: RB, CM, CT, BL, V-PL, CL, GB, J-FS, GDA, S Lavallée, S Lemieux, M-EB, GS. Writing and revision of manuscript: RB, CM, M-EB, BL, V-PL, JH, GS. Specimen banking and characterization: JH, GDA, S. Lavallée. Chemistry support: AM. Study supervision: M-EB, S Lemieux, AM, JH, GS.

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Correspondence to Guy Sauvageau.

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Bisaillon, R., Moison, C., Thiollier, C. et al. Genetic characterization of ABT-199 sensitivity in human AML. Leukemia 34, 63–74 (2020). https://doi.org/10.1038/s41375-019-0485-x

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