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

// Veronika Reidel 1 , Johanna Kauschinger 1 , Richard T. Hauch 1 , Catharina Müller-Thomas 1 , Niroshan Nadarajah 2 , Rainer Burgkart 3 , Burkhard Schmidt 4 , Dirk Hempel 5 , Anne Jacob 1 , Julia Slotta-Huspenina 6 , Ulrike Höckendorf 1 , Christian Peschel 1, 7 , Wolfgang Kern 2 , Torsten Haferlach 2 , Katharina S. Götze 1, 7 , Stefanie Jilg 1, * and Philipp J. Jost 1, 7, * 1 Medizinische Klinik für Hämatologie und Internistische Onkologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany 2 Munich Leukemia Laboratory (MLL), Munich, Germany 3 Klinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany 4 Gemeinschaftspraxis Hämato-Onkologie Pasing, Munich, Germany 5 Onkologisches Zentrum Donauwörth, Donauwörth, Germany 6 Institut für Pathologie, Klinikum rechts der Isar, Technische Universität München, Munich, Germany 7 Deutsche 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.