Abstract
Somatic mutations in
occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2
enzymes produce
-2-hydroxyglutarate (
2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for
AML is not known.
Well-characterized primary
,
, and
AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors.
caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2
inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of
AML cells. We provide evidence that the therapy sensitivity of
cells was caused by
2HG-mediated downregulation of expression of the DNA damage response gene
and not by altered redox responses due to metabolic alterations in
cells.
AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2
inhibitors during cytotoxic therapy decrease the efficacy of both agents in
AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in
AML.
.
