Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute myeloid leukemia

Genetic characterization of ABT-199 sensitivity in human AML

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Longo DL, et al. Acute myeloid leukemia. New En J Med. 2015.

  2. Arber DA, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  CAS  Google Scholar 

  3. Döhner H, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

    Article  Google Scholar 

  4. Schlenk RF, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. New Engl J Med. 2008;358:1909–18.

    Article  CAS  Google Scholar 

  5. Papaemmanuil E, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.

    Article  CAS  Google Scholar 

  6. Saygin C, Carraway HE. Emerging therapies for acute myeloid leukemia. J Hematol Oncol. 2017;10:93.

    Article  Google Scholar 

  7. Garnett MJ, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–5.

    Article  CAS  Google Scholar 

  8. Pabst C, et al. Identification of small molecules that support human leukemia stem cell activity ex vivo. Nat Methods. 2014;11:436–42.

    Article  CAS  Google Scholar 

  9. Simon L, et al. Chemogenomic landscape of RUNX1-mutated AML reveals importance of RUNX1 allele dosage in genetics and glucocorticoid sensitivity. Clin Cancer Res : Off J Am Assoc Cancer Res. 2017;23:6969–81.

    Article  CAS  Google Scholar 

  10. Falini B, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2007;109:874–85.

    Article  CAS  Google Scholar 

  11. Versluis J, et al. Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio. Leukemia. 2017;31:26–33.

    Article  CAS  Google Scholar 

  12. Souers AJ, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19:202–8.

    Article  CAS  Google Scholar 

  13. Robertson LE, et al. Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome. Leukemia. 1996;10:456–9.

    CAS  PubMed  Google Scholar 

  14. Konopleva M, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–17.

    Article  CAS  Google Scholar 

  15. Maiga A, et al. Transcriptome analysis of G protein-coupled receptors in distinct genetic subgroups of acute myeloid leukemia: identification of potential disease-specific targets. Blood Cancer J. 2016;6.

    Article  CAS  Google Scholar 

  16. Rose D, et al. Subtype-specific patterns of molecular mutations in acute myeloid leukemia. Leukemia. 2017;31:11–7.

    Article  CAS  Google Scholar 

  17. Thiede C, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107:4011–20.

    Article  CAS  Google Scholar 

  18. Fresquet V, et al. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. Blood. 2014;123:4111–9.

    Article  CAS  Google Scholar 

  19. Network C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. New Engl J Med. 2013;368:2059–74.

    Article  Google Scholar 

  20. Pati D, Zhang N, Plon SE. Linking sister chromatid cohesion and apoptosis: role of Rad21. Mol Cell Biol. 2002;22:8267–77.

    Article  CAS  Google Scholar 

  21. Atienza JM, et al. Suppression of RAD21 gene expression decreases cell growth and enhances cytotoxicity of etoposide and bleomycin in human breast cancer cells. Mol cancer Ther. 2005;4:361–8.

    CAS  PubMed  Google Scholar 

  22. Li J, et al. Downregulation of SMC1A inhibits growth and increases apoptosis and chemosensitivity of colorectal cancer cells. J Int Med Res. 2016;44:67–74.

    Article  Google Scholar 

  23. Mazumdar C, et al. Leukemia-associated cohesin mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation. Cell Stem cell. 2015.

  24. Carrington EM, et al. Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo. Cell death Differ. 2017;24:878–88.

    Article  CAS  Google Scholar 

  25. Esteve-Arenys A, et al. The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma. Oncogene. 2018.

  26. Bogenberger J, et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017;8:107206–22.

    Article  Google Scholar 

  27. Teh TCC, et al. Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1. Leukemia. 2018;32:303–12.

    Article  CAS  Google Scholar 

  28. D de Araujo A, et al. Bicyclic helical peptides as dual inhibitors selective for Bcl2A1 and Mcl-1 proteins. J Med Chem, 2018.

  29. Kotschy A, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538:477–82.

    Article  Google Scholar 

  30. Pan R, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4:362–75.

    Article  CAS  Google Scholar 

  31. DiNardo CD, et al. 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. Lancet Oncol. 2018;19:216–28.

    Article  CAS  Google Scholar 

  32. Chan SM, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21:178–84.

    Article  CAS  Google Scholar 

Download references

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).

Author information

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

Authors
  1. Richard Bisaillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Céline Moison
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Clarisse Thiollier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jana Krosl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie-Eve Bordeleau
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bernhard Lehnertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Vincent-Philippe Lavallée
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tara MacRae
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nadine Mayotte
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Caroline Labelle
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Geneviève Boucher
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jean-François Spinella
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Isabel Boivin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Giovanni D’Angelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Sylvie Lavallée
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Anne Marinier
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Sébastien Lemieux
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Josée Hébert
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Guy Sauvageau
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Guy Sauvageau.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0485-x

This article is cited by

Search

Advanced search

Quick links