Medizinische Universität Graz - Research portal
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SHR Neuro Cancer Cardio Lipid Metab Microb
Reidel, V; Kauschinger, J; Hauch, RT; Müller-Thomas, C; Nadarajah, N; Burgkart, R; Schmidt, B; Hempel, D; Jacob, A; Slotta-Huspenina, J; Höckendorf, U; Peschel, C; Kern, W; Haferlach, T; Götze, KS; Jilg, S; Jost, PJ.
Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile.
Oncotarget. 2018; 9(25):17270-17281
Doi: 10.18632/oncotarget.24775
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- Jost Philipp
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- 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.