Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations
HS Radomska, DS Bassères, R Zheng… - The Journal of …, 2006 - rupress.org
The Journal of experimental medicine, 2006•rupress.org
Mutations constitutively activating FLT3 kinase are detected in∼ 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 α (C/EBP α) 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 …
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 α (C/EBP α) 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 …
Mutations constitutively activating FLT3 kinase are detected in ∼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 α (C/EBPα) 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/EBPα 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/EBPα. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBPα may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.
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