Effect of FLT3 ligand on survival and disease phenotype in murine models harboring a FLT3 internal tandem duplication mutation

Emily J. Bailey, Amy S. Duffield, Sarah M. Greenblatt, Peter D. Aplan, Donald Small

Research output: Contribution to journalArticlepeer-review

Abstract

Many of the mutations contributing to leukemogenesis in acute myeloid leukemia have been identified. A common activating mutation is an internal tandem duplication (ITD) mutation in the FLT3 gene that is found in approximately 25% of patients and confers a poor prognosis. FLT3 inhibitors have been developed and have some efficacy, but patients often relapse. Levels of FLT3 ligand (FL) are significantly elevated in patients during chemotherapy and may be an important component contributing to relapse. We used a mouse model to investigate the possible effect of FL expression on leukemogenesis involving FLT3-ITD mutations in an in vivo system. FLT3ITD/ITD FL-/-(knockout) mice had a statistically significant increase in survival compared with FLT3ITD/ITD FL+/+ (wildtype) mice, most of which developed a fatal myeloproliferative neoplasm. These findings suggest that FL levels may have prognostic significance in human patients. We also studied the effect of FL expression on survival in a FLT3-ITD NUP98-HOX13 (NHD13) fusion mouse model. These mice develop an aggressive leukemia with short latency. We asked whether FL expression played a similar role in this context. The NUP98-HOX13 FLT3ITD/wt FL-/-mice did not have a survival advantage, compared with NUP98-HOX13 FLT3ITD/wt FL+/+ mice (normal FL levels). The loss of the survival advantage of the FL knockout group in the NUP98-HOX13 model suggests that adding a second mutation changes the effect of FL expression in the context of more aggressive disease.

Original languageEnglish (US)
Pages (from-to)218-226
Number of pages9
JournalComparative medicine
Volume63
Issue number3
StatePublished - Jun 2013

Keywords

  • AML
  • Acute myeloid leukemia; FL
  • FLT3 ligand; FLT3
  • FMS-like tyrosine kinase 3; ITD
  • Internal tandem duplication; MPN
  • Myeloproliferative neoplasm

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • veterinary(all)

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