title: Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations.
abstract: 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.
authors.affiliation: Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Radomska
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Bassères
authors.forename: Rui
authors.initials: R
authors.lastname: Zheng
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.forename: Tajhal
authors.initials: T
authors.lastname: Dayaram
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: David W
authors.initials: DW
authors.lastname: Sternberg
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lokker
authors.forename: Neill A
authors.initials: NA
authors.lastname: Giese
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Delmotte
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Donald
authors.initials: D
authors.lastname: Small
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
mesh_terms: 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
chemical_list: 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