Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression
Cancerous inhibitor of PP2A (CIP2A) at diagnosis of chronic myeloid leukemia is a critical determinant of disease progression
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DOI：
10.1182/blood-2010-08-304477
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发表时间：
2011-06-16
期刊：
影响因子：
20.3
通讯作者：
Clark, Richard E.
中科院分区：
文献类型：
--
作者：
Lucas, Claire M.;Harris, Robert J.;Clark, Richard E.
前瞻性识别慢性髓性白血病（CML）患者将进展为急变目前是不可能的。PP 2A是一种磷酸酶和肿瘤抑制因子，调节细胞增殖、分化和存活。PP 2A癌抑制剂（CIP 2A）是近年来发现的一种与乳腺癌和胃癌有关的PP 2A抑制剂。本研究的目的是研究CIP 2A是否在CML中发挥作用，以及PP 2A或其抑制蛋白CIP 2A或SET是否可以预测临床结果。在诊断CML时，以后进展为急变的患者的CIP 2A蛋白水平显著高于未进展的患者（P <0.0001），表明PP 2A在功能上是无活性的。我们表明，疾病进展的潜在机制是通过改变癌基因c-Myc的磷酸化。CIP 2A的敲低导致PP 2A活性增加、c-Myc水平降低以及BCR-ABL 1酪氨酸激酶活性降低。我们证明，诊断时的CIP 2A水平可以一致地预测将进展到爆炸危机的患者。这些数据表明CIP 2A在CML中具有生物学和临床重要性，并且可能是一种新的治疗靶点。（血。2011;117（24）：6660-6668）
Prospective identification of patients whose chronic myeloid leukemia (CML) will progress to blast crisis is currently not possible. PP2A is a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. Cancerous inhibitor of PP2A (CIP2A) is a recently described inhibitor of PP2A in breast and gastric cancer. The aim of this study was to investigate whether CIP2A played a role in CML and whether PP2A or its inhibitor proteins CIP2A or SET could predict clinical outcome. At the time of diagnosis of CML, patients who will later progress to blast crisis have significantly higher levels of CIP2A protein (P < .0001) than patients who do not progress, suggesting that PP2A is functionally inactive. We show that the potential mechanism for disease progression is via altered phosphorylation of the oncogene c-Myc. Knockdown of CIP2A results in increased PP2A activity, decreased c-Myc levels, and a decrease in BCR-ABL1 tyrosine kinase activity. We demonstrate that CIP2A levels at diagnosis can consistently predict patients who will progress to blast crisis. The data show that CIP2A is biologically and clinically important in CML and may be a novel therapeutic target. (Blood. 2011;117(24):6660-6668)