Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations.
Mutations constitutively activating FLT3 kinase are detected in approximately 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 alpha (C/EBPalpha) 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/EBPalpha 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/EBPalpha. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBPalpha may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.
Radomska
Hanna S
HS
Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02115, USA.
Bassères
Daniela S
DS
Zheng
Rui
R
Zhang
Pu
P
Dayaram
Tajhal
T
Yamamoto
Yukiya
Y
Sternberg
David W
DW
Lokker
Nathalie
N
Giese
Neill A
NA
Bohlander
Stefan K
SK
Schnittger
Susanne
S
Delmotte
Marie-Hélène
MH
Davis
Roger J
RJ
Small
Donald
D
Hiddemann
Wolfgang
W
Gilliland
D Gary
DG
Tenen
Daniel G
DG
D000368:Aged; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006098:Granulocytes / Q000473:pathology; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D022423:Myeloid Cells / Q000473:pathology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D011799:Quinazolines / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; D010879:Piperazines; D011799:Quinazolines; D012694:Serine; C464670:tandutinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human