title: Flt3-ITD alters chemotherapy response in vitro and in vivo in a p53-dependent manner.
abstract: 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.
  
  
  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.
authors.affiliation: Wake Forest University Health Sciences, Department of Internal Medicine, Section on Hematology and Oncology, Winston-Salem, NC 27157, USA. tspardee@wfubmc.edu
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Pardee
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000208:Acute Disease; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000008:administration & dosage; D015153:Blotting, Western; D003561:Cytarabine / Q000008:administration & dosage; D004249:DNA Damage; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D020440:Gene Duplication; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077157:Sorafenib; D016019:Survival Analysis; D020080:Tandem Repeat Sequences; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; D051788:Myeloid-Lymphoid Leukemia Protein; D009536:Niacinamide; D004317:Doxorubicin; D000077157:Sorafenib; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3