Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations

Hanna S. Radomska, Daniela S. Bassères, Rui Zheng, Pu Zhang, Tajhal Dayaram, Yukiya Yamamoto, David W. Sternberg, Nathalie Lokker, Neill A. Giese, Stefan K. Bohlander, Susanne Schnittger, Marie Hélène Delmotte, Roger J. Davis, Donald Small, Wolfgang Hiddemann, D. Gary Gilliland, Daniel G. Tenen

Research output: Contribution to journalArticlepeer-review

169 Scopus citations


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. JEM

Original languageEnglish
Pages (from-to)371-381
Number of pages11
JournalJournal of Experimental Medicine
Issue number2
StatePublished - 20 Feb 2006
Externally publishedYes


Dive into the research topics of 'Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations'. Together they form a unique fingerprint.

Cite this