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

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

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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. Access


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SIMILAR CONTENT BEING VIEWED BY OTHERS BH3 MIMETICS IN COMBINATION WITH NILOTINIB OR PONATINIB REPRESENT A PROMISING THERAPEUTIC STRATEGY IN BLAST PHASE CHRONIC MYELOID LEUKEMIA Article Open


access 15 November 2022 CD157 SIGNALING PROMOTES SURVIVAL OF ACUTE MYELOID LEUKEMIA CELLS AND MODULATES SENSITIVITY TO CYTARABINE THROUGH REGULATION OF ANTI-APOPTOTIC MCL-1 Article Open


access 27 October 2021 EFFECTIVE TUMOR CELL ABROGATION VIA VENETOCLAX-MEDIATED BCL-2 INHIBITION IN _KMT2A_-REARRANGED ACUTE B-LYMPHOBLASTIC LEUKEMIA Article Open access 01 July 2022


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PubMed Central  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Klinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany, J Schauwecker & R


Burgkart * Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany O Gorka & J Ruland * Gemeinschaftspraxis


Hämato-Onkologie Pasing, Munich, Germany B Schmidt Authors * S Jilg View author publications You can also search for this author inPubMed Google Scholar * V Reidel View author publications


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author inPubMed Google Scholar * P J Jost View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to P J Jost. ETHICS


DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies this paper on the Leukemia website SUPPLEMENTARY


INFORMATION SUPPLEMENTARY INFORMATION (PDF 1345 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 15 January 2015 * Revised: 24 June 2015 * Accepted: 25 June 2015 * Published: 08 July 2015 * Issue Date: January 2016 *


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