Flt3-ITD alters chemotherapy response in vitro and in vivo in a p53-dependent manner

Exp Hematol. 2011 Apr;39(4):473-485.e4. doi: 10.1016/j.exphem.2011.01.009. Epub 2011 Feb 1.


Objective: The FLT3 internal tandem duplication (Flt3-ITD) confers a worse prognosis for patients with acute myeloid leukemia (AML); however, the mechanisms involved are unknown. As AML is treated with cytarabine (Ara-C) and an anthracycline, we sought to determine the effects of the Flt3-ITD on response to these agents.

Materials and methods: A genetically defined mouse model of AML was used to examine the effects of the Flt3-ITD on response to cytarabine and doxorubicin in vitro and in vivo.

Results: In vitro, the Flt3-ITD conferred resistance to doxorubicin and doxorubicin plus Ara-C, but sensitivity to Ara-C alone. This resistance was reversible by the Flt3-ITD inhibitor sorafenib. The Flt3-ITD did not affect DNA damage levels after treatment, but was associated with increased levels of p53. The p53 response was critical to the observed changes as the Flt3-ITD had no effect on chemotherapy response in the setting of p53 null AML. In vivo, the Flt3-ITD accelerated engraftment that was partially reversible by Ara-C but not doxorubicin. Additionally, Ara-C provided a significant reduction in disease burden and a survival advantage that was not increased by the addition of doxorubicin. Doxorubicin alone led to only minimal disease reduction and no survival benefit.

Conclusions: These data demonstrate that the Flt3-ITD confers sensitivity to Ara-C, but resistance to doxorubicin in a manner that depends on p53. Thus, patients with Flt3-ITD positive AML may not benefit from treatment with an anthracycline.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benzenesulfonates / administration & dosage
  • Blotting, Western
  • Cytarabine / administration & dosage
  • DNA Damage
  • Disease Models, Animal
  • Doxorubicin / administration & dosage
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Gene Duplication
  • Humans
  • Leukemia, Myeloid / drug therapy
  • Leukemia, Myeloid / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Pyridines / administration & dosage
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sorafenib
  • Survival Analysis
  • Tandem Repeat Sequences*
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • fms-Like Tyrosine Kinase 3 / genetics*


  • Benzenesulfonates
  • Phenylurea Compounds
  • Pyridines
  • Tumor Suppressor Protein p53
  • Cytarabine
  • Myeloid-Lymphoid Leukemia Protein
  • Niacinamide
  • Doxorubicin
  • Sorafenib
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3