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Acute myeloid leukemia

HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia

Leukemia volume 31, pages 301–309 (2017)Cite this article

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Abstract

Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.

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Acknowledgements

We thank the patients who participated in the study. We acknowledge Evgeny Kulesskiy and the personnel of the High Throughput Biomedicine Unit and Minna Suvela, Pekka Ellonen, Aino Palva, Pirkko Mattila, Matti Kankainen and Henrikki Almusa from Institute for Molecular Medicine Finland (FIMM) Technology Centre, University of Helsinki, for their expert technical assistance. We acknowledge personnel of HUSLAB, Helsinki and TYKSLAB, Turku, for clinical cytogenetic, immunophenotypic and molecular genetic data. The Instrumentarium Foundation, Emil Aaltonen Foundation, Biomedicum Foundation, Paulo Foundation, Blood Disease Foundation and the Doctoral Programme in Clinical Research, University of Helsinki, funded MK. FinPharma Doctoral Program-Drug Discovery Section funded TP. The work has been supported by the Finnish Funding Agency for Technology and Innovation and Finnish Cancer Organizations.

Author contributions

MK designed the study, analyzed the data and wrote the manuscript; AK and SE performed sequence data analysis; MMM, TP and JS performed drug sensitivity testing and corresponding analysis; BY and DM performed DSS/sDSS analysis; AP designed and performed the RQ-PCR experiments and analyzed the data; MK, BTG, MH, YF, KR and KP collected the patient specimens and corresponding clinical data; and CH, KW and KP conceived the study, supervised the work and wrote the manuscript. All authors contributed to and approved the final manuscript.

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Author notes

  1. T Pemovska

    Present address: 8Current address: Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.,

  2. C A Heckman and K Porkka: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

    M Kontro & K Porkka

  2. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    A Kumar, M M Majumder, S Eldfors, A Parsons, T Pemovska, J Saarela, B Yadav, D Malani, O Kallioniemi, K Wennerberg & C A Heckman

  3. Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Y Fløisand

  4. Department of Hematology, Uppsala University Hospital, Uppsala, Sweden

    M Höglund

  5. Department of Clinical Hematology, Turku University Central Hospital, University of Turku, Turku, Finland

    K Remes

  6. Department of Clinical Science, Hematology Section, University of Bergen, Bergen, Norway

    B T Gjertsen

  7. Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway

    B T Gjertsen

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Correspondence to K Porkka.

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Competing interests

CAH has received research funding from Celgene and Pfizer; BTG has received research funding from Boehringer-Ingelheim Norge AS, and has been on advisory board for BerGenBio AS, Pfizer, Ariad, and Roche; MH has been on advisory boards for Janssen-Cilag and Akinion Pharmaceuticals; KP has received research funding from Celgene; and KW has received research funding from Pfizer.

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Kontro, M., Kumar, A., Majumder, M. et al. HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia. Leukemia 31, 301–309 (2017). https://doi.org/10.1038/leu.2016.222

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