BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein

被引:27
作者
Agarwal, Anupriya [1 ]
Mackenzie, Ryan J. [1 ]
Besson, Arnaud [2 ]
Jeng, Sophia [3 ]
Carey, Alyssa [1 ]
LaTocha, Dorian H. [1 ]
Fleischman, Angela G. [1 ]
Duquesnes, Nicolas [2 ]
Eide, Christopher A. [1 ,4 ]
Vasudevan, Kavin B. [1 ]
Loriaux, Marc M. [1 ,5 ]
Firpo, Eduardo [6 ]
Cortes, Jorge E. [7 ]
McWeeney, Shannon [3 ]
O'Hare, Thomas [8 ,9 ]
Roberts, James M. [6 ]
Druker, Brian J. [1 ,4 ]
Deininger, Michael W. [8 ,9 ]
机构
[1] Oregon Hlth & Sci Univ, Knight Canc Inst, Div Hematol & Med Oncol, Portland, OR 97239 USA
[2] Univ Toulouse, Canc Res Ctr Toulouse, INSERM, Unite Mixte Rech 1037, Toulouse, France
[3] Oregon Hlth & Sci Univ, Div Bioinformat & Computat Biol, Knight Canc Inst, Portland, OR 97239 USA
[4] Oregon Hlth & Sci Univ, Howard Hughes Med Inst, Portland, OR 97239 USA
[5] Oregon Hlth & Sci Univ, Dept Pathol, Knight Canc Inst, Portland, OR 97239 USA
[6] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA
[7] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
[8] Univ Utah, Div Hematol & Hematol Malignancies, Salt Lake City, UT USA
[9] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA
基金
美国国家卫生研究院;
关键词
DEPENDENT KINASE INHIBITOR; CHRONIC MYELOID-LEUKEMIA; SMALL-MOLECULE INHIBITORS; CELL-CYCLE PROGRESSION; BCR-ABL; STEM-CELLS; HEMATOPOIETIC PROGENITORS; SUBCELLULAR-LOCALIZATION; PHOSPHORYLATES P27(KIP1); TUMOR SUPPRESSION;
D O I
10.1182/blood-2013-04-497040
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Recent studies have revealed that p27, a nuclear cyclin-dependent kinase (Cdk) inhibitor and tumor suppressor, can acquire oncogenic activities upon mislocalization to the cytoplasm. To understand how these antagonistic activities influence oncogenesis, we dissected the nuclear and cytoplasmic functions of p27 in chronic myeloid leukemia (CML), a well-characterized malignancy caused by the BCR-ABL1 tyrosine kinase. p27 is predominantly cytoplasmic in CML and nuclear in normal cells. BCR-ABL1 regulates nuclear and cytoplasmic p27 abundance by kinase-dependent and -independent mechanisms, respectively. p27 knockdown in CML cell lines with predominantly cytoplasmic p27 induces apoptosis, consistent with a leukemogenic role of cytoplasmic p27. Accordingly, a p27 mutant (p27(ck-)) devoid of Cdk inhibitory nuclear functions enhances leukemogenesis in a murine CML model compared with complete absence of p27. In contrast, p27 mutations that enhance its stability (p27T1 87A) or nuclear retention (p27s1") attenuate leukemogenesis over wild-type p27, validating the tumor-suppressor function of nuclear p27 in CML. We conclude that BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. These findings suggest that cytoplasmic mislocalization of p27 despite BCR-ABL1 inhibition by tyrosine kinase inhibitors may contribute to drug resistance, and effective therapeutic strategies to stabilize nuclear p27 must also prevent cytoplasmic mislocalization.
引用
收藏
页码:3260 / 3273
页数:14
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