Impaired S-phase arrest in acute myeloid leukemia cells with a FLT3 internal tandem duplication treated with clofarabine

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
C H SeedhouseMonica Pallis

Abstract

Acute myeloid leukemia cells with an internal tandem duplication mutation of FLT3 (FLT3-ITD) have effective DNA repair mechanisms on exposure to drugs. Despite this, the phenotype is not associated with primary resistant disease. We show defects in the response of mutant FLT3 AML cells to the S-phase drug clofarabine that could account for the apparent contradiction. We studied responses of AML cells to clofarabine in vitro. When treated with a short pulse of clofarabine, FLT3-ITD-harboring MOLM-13 and MV4.11 cells undergo similar damage levels (gammaH2AX foci) to wild-type cells but have a better repair capability than wild-type cells. However, whereas the wild-type cells undergo rapid S-phase arrest, the S-phase checkpoint fails in mutant cells. Cell cycle arrest in response to DNA damage in S phase is effected via loss of the transcriptional regulator cdc25A. This loss is reduced or absent in clofarabine-treated FLT3 mutant cells. Furthermore, cdc25A message levels are maintained by the FLT3-ITD, such that message is reduced by 87.5% on exposure to FLT3 small interfering RNA. Primary FLT3-ITD samples from untreated patients also display impaired cell cycle arrest and show enhanced sensitivity on prolonged treatment with clof...Continue Reading

Citations

Oct 12, 2012·Cancer Chemotherapy and Pharmacology·Oystein BruserudKimberley Joanne Hatfield
Jun 19, 2013·BMC Pharmacology & Toxicology·Monica PallisNigel Russell
Nov 23, 2017·Frontiers in Oncology·Martino Marco Gabra, Leonardo Salmena

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