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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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DOI
PMC
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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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
ISSN (print) / ISBN
0022-1007
e-ISSN
1540-9538
Zeitschrift
Journal of Experimental Medicine
Quellenangaben
Band: 203,
Heft: 2,
Seiten: 371-381
Verlag
Rockefeller University Press
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed