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J Exp Med. 2006 Feb 20;203(2):371-81. Epub 2006 Jan 30.

Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations.

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  • 1Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02115, USA.

Abstract

Mutations constitutively activating FLT3 kinase are detected in approximately 30% of acute myelogenous leukemia (AML) patients and affect downstream pathways such as extracellular signal-regulated kinase (ERK)1/2. We found that activation of FLT3 in human AML inhibits CCAAT/enhancer binding protein alpha (C/EBPalpha) function by ERK1/2-mediated phosphorylation, which may explain the differentiation block of leukemic blasts. In MV4;11 cells, pharmacological inhibition of either FLT3 or MEK1 leads to granulocytic differentiation. Differentiation of MV4;11 cells was also observed when C/EBPalpha mutated at serine 21 to alanine (S21A) was stably expressed. In contrast, there was no effect when serine 21 was mutated to aspartate (S21D), which mimics phosphorylation of C/EBPalpha. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBPalpha may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.

PMID:
16446383
[PubMed - indexed for MEDLINE]
PMCID:
PMC2118199
Free PMC Article
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