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 Blood, 1 March 2004, Vol. 103, No. 5, pp. 1883-1890.
Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2003-06-1978.

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NEOPLASIA

Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBP{alpha} expression

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

From the Departments of Oncology, Pediatrics, and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.

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 {alpha} (C/EBP{alpha}) 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/EBP{alpha} 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/EBP{alpha} was also able to overcome FLT3/ITD-mediated differentiation block, further proving the importance of C/EBP{alpha} in this process.


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