Oncotarget

Research Papers: Autophagy and Cell Death:

Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile

Veronika Reidel, Johanna Kauschinger, Richard T. Hauch, Catharina Müller-Thomas, Niroshan Nadarajah, Rainer Burgkart, Burkhard Schmidt, Dirk Hempel, Anne Jacob, Julia Slotta-Huspenina, Ulrike Höckendorf, Christian Peschel, Wolfgang Kern, Torsten Haferlach, Katharina S. Götze, Stefanie Jilg and Philipp J. Jost _

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Oncotarget. 2018; 9:17270-17281. https://doi.org/10.18632/oncotarget.24775

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Abstract

Veronika Reidel1, Johanna Kauschinger1, Richard T. Hauch1, Catharina Müller-Thomas1, Niroshan Nadarajah2, Rainer Burgkart3, Burkhard Schmidt4, Dirk Hempel5, Anne Jacob1, Julia Slotta-Huspenina6, Ulrike Höckendorf1, Christian Peschel1,7, Wolfgang Kern2, Torsten Haferlach2, Katharina S. Götze1,7, Stefanie Jilg1,* and Philipp J. Jost1,7,*

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

2Munich Leukemia Laboratory (MLL), Munich, Germany

3Klinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

4Gemeinschaftspraxis Hämato-Onkologie Pasing, Munich, Germany

5Onkologisches Zentrum Donauwörth, Donauwörth, Germany

6Institut für Pathologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

7Deutsche Konsortium für translationale Krebsforschung (DKTK) of the German Cancer Research Center (DKFZ), Heidelberg, Germany

*These authors contributed equally to this work

Correspondence to:

Philipp J. Jost, email: philipp.jost@tum.de

Keywords: apoptosis; BCL-2 family; ABT-199; myelodysplastic syndromes; myeloid malignancy; Autophagy

Received: November 14, 2017     Accepted: February 25, 2018     Published: April 03, 2018

ABSTRACT

Somatic mutations in genes such as ASXL1, RUNX1, TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL-2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro-apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death. Supporting the potential for ABT-199 treatment in MDS, high-risk MDS patient samples specifically underwent cell death in response to ABT-199 even when harbouring mutations in ASXL1, RUNX1, TP53 or EZH2. ABT-199 effectively targeted the stem- and progenitor compartment in advanced MDS harbouring mutations in ASXL1, RUNX1, TP53 or EZH2 and even proved effective in patients harbouring more than one of the defined high-risk mutations. Moreover, we utilized the protein abundance of BCL-2 family members in primary patient samples using flow cytometry as a biomarker to predict ABT-199 treatment response. Our data demonstrate that ABT-199 effectively induces apoptosis in progenitors of high-risk MDS/sAML despite the presence of adverse genetic mutations supporting the notion that pro-apoptotic intervention will hold broad therapeutic potential in high-risk MDS patients with poor prognosis.


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