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

被引:165
作者
Radomska, HS
Bassères, DS
Zheng, R
Zhang, P
Dayaram, T
Yamamoto, Y
Sternberg, DW
Lokker, N
Giese, NA
Bohlander, SK
Schnittger, S
Delmotte, MH
Davis, RJ
Small, D
Hiddemann, W
Gilliland, DG
Tenen, DG [1 ]
机构
[1] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA
[3] Johns Hopkins Univ, Sch Med, Baltimore, MD 21231 USA
[4] Millennium Pharmaceut Inc, San Francisco, CA 94080 USA
[5] GSF Munich, Natl Res Ctr Environm & Hlth, Lab Leukemia Diagnost, Dept Internal Med 3, D-81377 Munich, Germany
[6] GSF Munich, Natl Res Ctr Environm & Hlth, CCG Acute Leukemias, D-81377 Munich, Germany
[7] Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01655 USA
[8] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01655 USA
关键词
D O I
10.1084/jem.20052242
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Mutations constitutively activating FLT3 kinase are detected in similar to 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/EBP alpha) 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/EBP alpha 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/EBP alpha. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBP alpha may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies.
引用
收藏
页码:371 / 381
页数:11
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