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

• Published in: Oncotarget Vol. 9; no. 25; pp. 17270 - 17281
• Main Authors: Reidel, Veronika, Kauschinger, Johanna, Hauch, Richard T, Müller-Thomas, Catharina, Nadarajah, Niroshan, Burgkart, Rainer, Schmidt, Burkhard, Hempel, Dirk, Jacob, Anne, Slotta-Huspenina, Julia, Höckendorf, Ulrike, Peschel, Christian, Kern, Wolfgang, Haferlach, Torsten, Götze, Katharina S, Jilg, Stefanie, Jost, Philipp J
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 03-04-2018
• Subjects: Research Paper: Autophagy and Cell Death; apoptosis; BCL-2 family; myeloid malignancy; Autophagy; ABT-199; myelodysplastic syndromes
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.24775

Somatic mutations in genes such as
,
,
or
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
,
,
or
. ABT-199 effectively targeted the stem- and progenitor compartment in advanced MDS harbouring mutations in
,
,
or
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.