TY - JOUR
T1 - Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations
AU - Radomska, Hanna S.
AU - Bassères, Daniela S.
AU - Zheng, Rui
AU - Zhang, Pu
AU - Dayaram, Tajhal
AU - Yamamoto, Yukiya
AU - Sternberg, David W.
AU - Lokker, Nathalie
AU - Giese, Neill A.
AU - Bohlander, Stefan K.
AU - Schnittger, Susanne
AU - Delmotte, Marie Hélène
AU - Davis, Roger J.
AU - Small, Donald
AU - Hiddemann, Wolfgang
AU - Gilliland, D. Gary
AU - Tenen, Daniel G.
PY - 2006/2/20
Y1 - 2006/2/20
N2 - 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
AB - 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
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U2 - 10.1084/jem.20052242
DO - 10.1084/jem.20052242
M3 - Article
C2 - 16446383
AN - SCOPUS:33344455424
SN - 0022-1007
VL - 203
SP - 371
EP - 381
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -