1] Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA [2] Division of Hematology and Internal Medicine, Department of Oncology, San Luigi Hospital, University of Turin, Turin, Italy.
Division of Hematology and Internal Medicine, Department of Oncology, San Luigi Hospital, University of Turin, Turin, Italy.
Leukemia. 2014 Jun;28(6):1326-33. doi: 10.1038/leu.2013.370. Epub 2013 Dec 9.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the t(9;22) translocation coding for the chimeric protein p210 BCR-ABL. The tumor suppressor phosphatase and tensin homolog (PTEN) has recently been shown to have a critical role in the pathogenesis of CML. Nuclear localization and proper nuclear-cytoplasmic shuttling are crucial for PTEN's tumor suppressive function. In this study, we show that BCR-ABL enhances HAUSP-induced de-ubiquitination of PTEN in turn favoring its nuclear exclusion. We further demonstrate that BCR-ABL physically interacts with and phosphorylates HAUSP on tyrosine residues to trigger its activity. Importantly, we also find that PTEN delocalization induced by BCR-ABL does not occur in the leukemic stem cell compartment due to high levels of PML, a potent inhibitor of HAUSP activity toward PTEN. We therefore identify a new proto-oncogenic mechanism whereby BCR-ABL antagonizes the nuclear function of the PTEN tumor suppressor, with important therapeutic implications for the eradication of CML minimal residual disease.
慢性髓性白血病（CML）是一种骨髓增生性疾病，其特征在于 t（9；22）易位编码嵌合蛋白 p210 BCR-ABL。肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）最近被证明在 CML 的发病机制中具有关键作用。核定位和适当的核质穿梭对于 PTEN 的肿瘤抑制功能至关重要。在这项研究中，我们表明 BCR-ABL 增强了 HAUSP 诱导的 PTEN 去泛素化，从而有利于其核排斥。我们进一步证明 BCR-ABL 与 HAUSP 相互作用并在酪氨酸残基上磷酸化 HAUSP，从而触发其活性。重要的是，我们还发现由于 PML 水平高，BCR-ABL 诱导的 PTEN 去定位不会发生在白血病干细胞区室中，因为 PML 是 HAUSP 对 PTEN 活性的有效抑制剂。因此，我们确定了一种新的原癌基因机制，即 BCR-ABL 拮抗 PTEN 肿瘤抑制因子的核功能，这对根除 CML 微小残留病具有重要的治疗意义。
