Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPα expression

Rui Zheng, Alan D. Friedman, Mark Levis, Li Li, Edward G. Weir, Donald Small

Research output: Contribution to journalArticlepeer-review

Abstract

Constitutively activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in approximately one third of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Altered FLT3 signaling leads to antiapoptotic and proliferative signaling pathways. We recently showed that these mutations can also contribute to the differentiation arrest that characterizes leukemia. In this report we investigated the mechanism by which internal tandem duplication (ITD) mutation of FLT3 signaling blocks differentiation. Normally, myeloid differentiation requires the induction of CCAAT/enhancer-binding protein α (C/EBPα) and PU.1 expression. Expression of both genes was repressed by FLT3/ITD signaling in 32Dcl3 (32D) cells and this repression was overcome by treatment with a FLT3 inhibitor, allowing differentiation to proceed. We also observed increased expression of C/ESP2α and PU.1 accompanied by signs of differentiation in 2 of 3 primary AML samples from patients with FLT3/ITD mutations receiving a FLT3 inhibitor, CEP-701, as part of a clinical trial. Forced expression of C/ESPα was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/ESPα in this process.

Original languageEnglish (US)
Pages (from-to)1883-1890
Number of pages8
JournalBlood
Volume103
Issue number5
DOIs
StatePublished - Mar 1 2004

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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