Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile
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Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile. / 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.
in: ONCOTARGET, Jahrgang 9, Nr. 25, 03.04.2019, S. 17270-17281.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile
AU - Reidel, Veronika
AU - Kauschinger, Johanna
AU - Hauch, Richard T
AU - Müller-Thomas, Catharina
AU - Nadarajah, Niroshan
AU - Burgkart, Rainer
AU - Schmidt, Burkhard
AU - Hempel, Dirk
AU - Jacob, Anne
AU - Slotta-Huspenina, Julia
AU - Höckendorf, Ulrike
AU - Peschel, Christian
AU - Kern, Wolfgang
AU - Haferlach, Torsten
AU - Götze, Katharina S
AU - Jilg, Stefanie
AU - Jost, Philipp J
PY - 2019/4/3
Y1 - 2019/4/3
N2 - 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.
AB - 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.
U2 - 10.18632/oncotarget.24775
DO - 10.18632/oncotarget.24775
M3 - SCORING: Journal article
C2 - 29707107
VL - 9
SP - 17270
EP - 17281
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 25
ER -