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Acute myeloid leukemia

Elevated expression of S100A8 and S100A9 correlates with resistance to the BCL-2 inhibitor venetoclax in AML

Leukemia volume 33, pages 2548–2553 (2019)Cite this article

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The selective B-cell lymphoma/leukemia 2 (BCL-2) protein antagonist venetoclax (ABT-199) is an effective treatment for elderly unfit acute myeloid leukemia (AML) patients, particularly in combination with low-dose cytarabine or a hypomethylating agent [1]. Nevertheless, not all AML patients respond to venetoclax-based therapy and many responding patients eventually become resistant. The identification of molecular indicators of venetoclax sensitivity and primary resistance is therefore important to distinguish patients who would benefit from venetoclax-based therapy, monitor resistance to treatment, and design novel combinatorial therapies that can overcome resistance.

Besides expression levels of anti-apoptotic BCL-2 family members, very little is known about the determinants of venetoclax sensitivity and resistance [2, 3]. Studies suggest that AML patients with a mutation to IDH1/2, SRSF2, or ZRSR2 are likely to respond to venetoclax [4,5,6], while patients with a mutation to the protein tyrosine phosphatase PTPN11 or an internal tandem duplication to FLT3 are likely to be resistant [6]. Several preclinical studies have investigated promising combinations to overcome venetoclax resistance in AML, including inhibition of MCL-1 [7], Janus-activated kinase 1/2 (JAK1/2) [8], and cyclin-dependent kinases (CDKs) [9]. In this study, we aimed to identify molecular indicators for primary resistance to venetoclax and potential combination therapies to sensitize AML cells to venetoclax treatment.

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Acknowledgements

We thank the patients and healthy donors for their samples and the research staff of the FIMM Technology Center, High Throughput Biomedicine Unit, the Breeze team, Hematology Research Unit, Minna Suvela and Siv Knaappila for their excellent technical assistance. We thank colleagues, Dr. Jarno Kivioja and  Dr. Heikki Kuusanmäki for their critical comments on the manuscript. The study was financially supported by the Finnish Funding Agency for Technology and Innovation - Tekes, the European Regional Development Funds, as well as grants from the Academy of Finland, Cancer Society of Finland and Sigrid Juselius Foundation. RK was supported by grants from the Cancer Society of Finland, K. Albin Johanssons stiftelse, Ida Montin Foundation, Orion Research Foundation, Oncology Society of Finland, and Väre Foundation for pediatric cancer research. AK received an EMBO short-term fellowship award and grants from the Cancer Society of Finland and Finnish Hematology Association. LH was supported by funding from the Integrated Life Sciences (ILS) doctoral program University of Helsinki, and a grant from the Cancer Society of Finland.

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  1. These authors contributed equally: Riikka Karjalainen, Minxia Liu

Authors and Affiliations

  1. Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland

    Riikka Karjalainen, Minxia Liu, Ashwini Kumar, Liye He, Disha Malani, Alun Parsons, Olli Kallioniemi & Caroline A. Heckman

  2. Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland

    Mika Kontro & Kimmo Porkka

  3. Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

    Mika Kontro & Kimmo Porkka

Authors
  1. Riikka Karjalainen
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Contributions

RK and ML designed the study, performed experiments, and analyzed the data; AK performed data analysis (collection, preprocessing, visualization, and machine learning). AP performed the RT-qPCR experiments and analysis. LH performed the drug combination synergy analysis. DM provided drug-sensitivity testing data in AML cell lines. MK and KP provided patient specimens and obtained institutional review board approval. CAH supervised the study. RK wrote the manuscript. ML, AK, and CAH participated in the writing and editing of the manuscript. All authors contributed to and approved the final version of the manuscript.

Corresponding author

Correspondence to Caroline A. Heckman.

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Conflict of interest

OK is a co-founder and a board member of Medisapiens and Sartar Therapeutics. He has received royalty on patents licensed from UC to Vysis-Abbot. His research group has a Vinnova-funded collaborative program with Astra-Zeneca, Labcyte, Takara Biosciences, and Pelago. KP has honoraria and grant support from Bristol-Myers Squibb, Celgene, Novartis, and Pfizer. CAH has received funding from Celgene, Orion Pharma, Novartis, Oncopeptides, and the Innovative Medicines Initiatives 2 project HARMONY. The other authors declare that they have no conflict of interest.

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Karjalainen, R., Liu, M., Kumar, A. et al. Elevated expression of S100A8 and S100A9 correlates with resistance to the BCL-2 inhibitor venetoclax in AML. Leukemia 33, 2548–2553 (2019). https://doi.org/10.1038/s41375-019-0504-y

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