BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein
BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein
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DOI：
10.1182/blood-2013-04-497040
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发表时间：
2014-11-20
期刊：
影响因子：
20.3
通讯作者：
Deininger, Michael W.
中科院分区：
文献类型：
--
作者：
Agarwal, Anupriya;Mackenzie, Ryan J.;Deininger, Michael W.
最近的研究表明，p27 是一种核细胞周期蛋白依赖性激酶 (Cdk) 抑制剂和肿瘤抑制因子，在错误定位到细胞质后可以获得致癌活性。为了了解这些拮抗活性如何影响肿瘤发生，我们剖析了慢性粒细胞白血病 (CML) 中 p27 的核和细胞质功能，慢性粒细胞白血病是一种由 BCR-ABL1 酪氨酸激酶引起的明确特征的恶性肿瘤。 p27 在 CML 中主要存在于细胞质中，而在正常细胞中则主要存在于细胞核中。 BCR-ABL1 分别通过激酶依赖性和独立性机制调节核和细胞质 p27 丰度。在以细胞质 p27 为主的 CML 细胞系中，p27 敲低会诱导细胞凋亡，这与细胞质 p27 的致白血病作用一致。因此，与完全不存在p27相比，缺乏Cdk抑制性核功能的p27突变体(p27(ck-))可增强小鼠CML模型中的白血病发生。相反，与野生型 p27 相比，增强其稳定性 (p27T1 87A) 或核保留 (p27s1") 的 p27 突变可减弱白血病发生，从而验证了核 p27 在 CML 中的肿瘤抑制功能。我们得出结论，BCR-ABL1 激酶依赖和独立机制将 p27 从核肿瘤抑制基因转化为细胞质癌基因。这些发现表明，细胞质错误定位尽管酪氨酸激酶抑制剂抑制了 BCR-ABL1，但 p27 的表达可能会导致耐药性，稳定核 p27 的有效治疗策略还必须防止细胞质错误定位。
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.