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- Title
Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations.
- Authors
Radomska, Hanna S; Bassères, Daniela S; Zheng, Rui; Zhang, Pu; Dayaram, Tajhal; Yamamoto, Yukiya; Sternberg, David W; Lokker, Nathalie; Giese, Neill A; Bohlander, Stefan K; Schnittger, Susanne; Delmotte, Marie-Hélène; Davis, Roger J; Small, Donald; Hiddemann, Wolfgang; Gilliland, D Gary; Tenen, Daniel G
- 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.
- Publication
The Journal of experimental medicine, 2006, Vol 203, Issue 2, p371
- ISSN
0022-1007
- Publication type
Journal Article
- DOI
10.1084/jem.20052242