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2017 ; 58
(ä): 91-97
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Epigenetic drug combination induces remission in mouse xenograft models of
pediatric acute myeloid leukemia
#MMPMID28505595
Gopalakrishnapillai A
; Kolb EA
; McCahan SM
; Barwe SP
Leuk Res
2017[Jul]; 58
(ä): 91-97
PMID28505595
show ga
Aberrations in epigenetic modifications contribute to leukemogenesis in childhood
acute myeloid leukemia (AML). We combined DNA hypomethylating agent azacitidine
with histone deacetylase inhibitor panobinostat in preclinical models of
childhood AML. Synergistic cytotoxic effect upon treatment with azacitidine and
panobinostat with combination indices <1.0 was observed. Azacitidine and
panobinostat increased median survival by 26 and 6days respectively in MV4;11
xenografted mice. Mice treated with both drugs showed a drastic reduction in
leukemic burden leading to complete remission sustained for the duration of the
experimental period lasting more than 519days. Reduced leukemic burden and
prolonged survival was also observed in AML-193 xenografted mice treated with
azacitidine-panobinostat combination. Differential gene expression profiling was
performed on AML cells treated with azacitidine, panobinostat or
azacitidine-panobinostat combination. Functional mapping of transcripts uniquely
regulated by the azacitidine-panobinostat combination in MV4;11 cells identified
p53 as an upstream regulator. A comparison of the uniquely modulated transcripts
by azacitidine-panobinostat combination in MV4;11 cells versus AML-193 and THP-1
cells, bearing mutated p53, also revealed p53 as the topmost upstream regulator.
Finally, expression of mutant p53 in MV4;11 cells reduced sensitivity to
azacitidine-panobinostat combination, suggesting that p53 may be a predictor of
response to epigenetic therapy in pediatric AML.