Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition

Patrick Brown, Soheil Meshinchi, Mark Levis, Todd A. Alonzo, Robert Gerbing, Beverly Lange, Robert Arceci, Donald Small

Research output: Contribution to journalArticlepeer-review

Abstract

Pediatric acute myelogenous leukemia (AML) has a poor prognosis, and novel therapies are needed. The FLT3 tyrosine kinase represents a promising target in pediatric AML. FLT3 is constitutively activated either by an internal tandem duplication (ITD) or by a point mutation (PM) in 17% to 24% of pediatric AML cases. Autocrine stimulation of wild-type (WT) FLT3 by coexpressed FLT3 ligand (FL) occurs in many other cases. FLT3/ITD mutations confer a particularly poor prognosis in pediatric AML patients. Inhibitors of FLT3 are being tested in adult AML patients, with promising preliminary results. In this study, cytotoxicity and apoptosis assays were performed on 44 diagnostic pediatric AML blast samples (14 FLT3/WT, 15 FLT3/ITD, 15 FLT3/PM) using CEP-701, a potent and selective FLT3 inhibitor. Pronounced cytotoxicity and induction of apoptosis were observed in a higher percentage of FLT3/ITD samples (93%) than FLT3/PM (27%) or FLT3/WT (29%). The cytotoxicity was greatest in samples with a high FLT3/ITD mutant-to-wild-type allelic ratio. The addition of FL enhanced the survival and augmented the sensitivity to FLT3 inhibition for the CEP-701-responsive subset of FLT3/WT and FLT3/PM samples. Clinical testing of FLT3 inhibitors as molecularly targeted agents for the improvement of outcome of pediatric AML patients is warranted.

Original languageEnglish (US)
Pages (from-to)1841-1849
Number of pages9
JournalBlood
Volume104
Issue number6
DOIs
StatePublished - Sep 15 2004

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition'. Together they form a unique fingerprint.

Cite this