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Myelodysplastic syndrome

Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients

Leukemia volume 30, pages 112–123 (2016)Cite this article

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Abstract

Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34+ cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.

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Acknowledgements

We thank T Haferlach from the Munich Leukemia Laboratory (MLL) for providing gene expression data. We thanks T Haferlach from MLL and M Zingerle from the Gemeinschaftspraxis Hämato-Onkologie Pasing for providing MDS samples and clinical data and J Tuebel from the Klinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar for technical support. PJJ was supported by a Max Eder-Program grant from the Deutsche Krebshilfe (program #111738), a Human Frontiers Science Program grant (program #RGY0073/2012), a German Jose Carreras Leukemia Foundation grant (DJCLS R 12/22), and a research grant from the Deutsche Forschungsgemeinschaft, Forschergruppe FOR2036 and Novartis for travel support. RAJO was supported by the German Research Foundation (DFG grants OO 8/5, OO 8/9, and FOR 2033)). RAJO and KSG were supported by the German Jose Carreras Leukemia Foundation grant (DJCLS R 11/12). KSG was supported by the German Research Foundation (Go 713/2-1) and the Deutsche Konsortium für Translationale Krebsforschung (DKTK) of the German Cancer Center (DKFZ). We thank Abbvie for supplying ABT-199.

Author contributions

PJJ conceived and supervised the project, analyzed the data and wrote the manuscript. SJ performed the experiments, analyzed the data and wrote the manuscript. KG provided primary samples and clinical data and gave conceptual advice. VR, JK, UH, OG and CH performed experiments. JS, BS, RB, CM-T, H-JK, RAJO, JR and CP provided primary samples and clinical data, and gave conceptual advice.

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Authors and Affiliations

  1. III. Medizinische Klinik für Hämatologie und Internistische Onkologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    S Jilg, V Reidel, C Müller-Thomas, J König, U Höckendorf, C Huberle, H-J Kolb, C Peschel, R A J Oostendorp, K S Götze & P J Jost

  2. Klinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany,

    J Schauwecker & R Burgkart

  3. Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    O Gorka & J Ruland

  4. Gemeinschaftspraxis Hämato-Onkologie Pasing, Munich, Germany

    B Schmidt

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Jilg, S., Reidel, V., Müller-Thomas, C. et al. Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients. Leukemia 30, 112–123 (2016). https://doi.org/10.1038/leu.2015.179

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