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Radomska, H.S.* ; Bassères, D.S.* ; Zheng, R.* ; Zhang, P.* ; Dayaram, T.* ; Yamamoto, Y.* ; Sternberg, D.W.* ; Lokker, N.* ; Giese, N.A.* ; Bohlander, S.K. ; Schnittger, S. ; Delmotte, M.H.* ; Davis, R.J.* ; Small, D.* ; Hiddemann, W. ; Gilliland, D.G.* ; Tenen, D.G.*

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

J. Exp. Med. 203, 371-381 (2006)
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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 © The Rockefeller University Press.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0022-1007
e-ISSN 1540-9538
Journal Journal of Experimental Medicine
Quellenangaben Volume: 203, Issue: 2, Pages: 371-381 Article Number: , Supplement: ,
Publisher Rockefeller University Press
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)