Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3-and KIT-Driven Leukemogenesis

被引：56

作者：

Chatterjee, Anindya ^{[1
]}

Ghosh, Joydeep ^{[1
,2
]}

Ramdas, Baskar ^{[1
]}

Mali, Raghuveer Singh ^{[1
]}

Martin, Holly ^{[1
,3
]}

Kobayashi, Michihiro ^{[1
]}

Vemula, Sasidhar ^{[1
]}

Canela, Victor H. ^{[1
]}

Waskow, Emily R. ^{[1
]}

Visconte, Valeria ^{[6
]}

Tiu, Ramon V. ^{[6
]}

Smith, Catherine C. ^{[7
]}

Shah, Neil ^{[7
]}

Bunting, Kevin D. ^{[8
]}

Boswell, H. Scott ^{[4
]}

Liu, Yan ^{[1
]}

Chan, Rebecca J. ^{[1
,3
]}

Kapur, Reuben ^{[1
,2
,3
,5
]}

机构：

[1] Indiana Univ Sch Med, Herman B Wells Ctr Pediat Res, Dept Pediat, Indianapolis, IN 46202 USA

[2] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA

[3] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[4] Indiana Univ Sch Med, Dept Med, Div Hematol Oncol, Indianapolis, IN 46202 USA

[5] Indiana Univ Sch Med, Dept Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[6] Cleveland Clin, Taussig Canc Inst, Dept Translat Hematol & Oncol Res, Cleveland, OH 44195 USA

[7] Univ Calif San Francisco, Div Hematol Oncol, San Francisco, CA 94143 USA

[8] Emory Univ, Sch Med, Dept Pediat, Aflac Canc & Blood Disorders Ctr, Atlanta, GA 30322 USA

来源：

CELL REPORTS | 2014年 / 9卷 / 04期

关键词：

ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; FOCAL ADHESION KINASE; SMALL-MOLECULE INHIBITOR; CONSTITUTIVE ACTIVATION; SIGNAL TRANSDUCER; TUMOR-GROWTH; P21-ACTIVATED KINASE; POOR-PROGNOSIS; CANCER CELLS;

D O I：

10.1016/j.celrep.2014.10.039

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective. Although Stat5 has been implicated in regulating several myeloid and lymphoid malignancies, how precisely Stat5 regulates leukemogenesis, including its nuclear translocation to induce gene transcription, is poorly understood. In leukemic cells, we show constitutive activation of focal adhesion kinase (FAK) whose inhibition represses leukemogenesis. Downstream of FAK, activation of Rac1 is regulated by RacGEF Tiam1, whose inhibition prolongs the survival of leukemic mice. Inhibition of the Rac1 effector PAK1 prolongs the survival of leukemic mice in part by inhibiting the nuclear translocation of Stat5. These results reveal a leukemic pathway involving FAK/Tiam1/Rac1/PAK1 and demonstrate an essential role for these signaling molecules in regulating the nuclear translocation of Stat5 in leukemogenesis.

引用

页码：1333 / 1348

页数：16

共 48 条

[1]

Prolactin-stimulated activation of ERK1/2 mitogen-activated protein kinases is controlled by PI3-kinase/Rac/PAK signaling pathway in breast cancer cells [J].