Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Blood. 2010 Jan 21;115(3):626-35. doi: 10.1182/blood-2009-06-228130. Epub 2009 Nov 18.
The tumor suppressor gene phosphatase and tensin homolog (PTEN) is inactivated in many human cancers. However, it is unknown whether PTEN functions as a tumor suppressor in human Philadelphia chromosome-positive leukemia that includes chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL) and is induced by the BCR-ABL oncogene. By using our mouse model of BCR-ABL-induced leukemias, we show that Pten is down-regulated by BCR-ABL in leukemia stem cells in CML and that PTEN deletion causes acceleration of CML development. In addition, overexpression of PTEN delays the development of CML and B-ALL and prolongs survival of leukemia mice. PTEN suppresses leukemia stem cells and induces cell-cycle arrest of leukemia cells. Moreover, PTEN suppresses B-ALL development through regulating its downstream gene Akt1. These results demonstrate a critical role of PTEN in BCR-ABL-induced leukemias and suggest a potential strategy for the treatment of Philadelphia chromosome-positive leukemia.
抑癌基因磷酸酶和张力蛋白同源物（PTEN）在许多人类癌症中失活。然而，目前尚不清楚 PTEN 是否在人类费城染色体阳性白血病（包括慢性髓系白血病（CML）和 B 细胞急性淋巴细胞白血病（B-ALL））中作为肿瘤抑制因子发挥作用，而费城染色体阳性白血病是由 BCR-ABL 癌基因诱导的。通过使用我们的 BCR-ABL 诱导白血病的小鼠模型，我们表明 Pten 在 CML 中的白血病干细胞中被 BCR-ABL 下调，并且 PTEN 缺失导致 CML 发展加速。此外，PTEN 的过表达延迟了 CML 和 B-ALL 的发展，并延长了白血病小鼠的存活时间。PTEN 抑制白血病干细胞并诱导白血病细胞的细胞周期停滞。此外，PTEN 通过调节其下游基因 Akt1 来抑制 B-ALL 的发展。这些结果表明 PTEN 在 BCR-ABL 诱导的白血病中具有重要作用，并为治疗费城染色体阳性白血病提供了一种潜在的策略。
