Division of Hematology-Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Leukemia. 2010 Aug;24(8):1397-405. doi: 10.1038/leu.2010.131. Epub 2010 Jun 10.
Signal transducer and activator of transcription-5 (STAT5) is a critical transcription factor for normal hematopoiesis and its sustained activation is associated with hematologic malignancy. A persistently active mutant of STAT5 (STAT5a(S711F)) associates with Grb2-associated binding protein 2 (Gab2) in myeloid leukemias and promotes growth in vitro through AKT activation. Here we have retrovirally transduced wild-type or Gab2(-/-) mouse bone marrow cells expressing STAT5a(S711F) and transplanted into irradiated recipient mice to test an in vivo myeloproliferative disease model. To target Gab2-independent AKT/mTOR activation, we treated wild-type mice separately with rapamycin. In either case, mice lacking Gab2 or treated with rapamycin showed attenuated myeloid hyperplasia and modestly improved survival, but the effects were not cytotoxic and were reversible. To improve on this approach, we combined in vitro targeting of STAT5-mediated AKT/mTOR using rapamycin with inhibition of the STAT5 direct target genes bcl-2 and bcl-X(L) using ABT-737. Striking synergy with both drugs was observed in mouse BaF3 cells expressing STAT5a(S711F), TEL-JAK2 or BCR-ABL and in the relatively single agent-resistant human BCR-ABL-positive K562 cell line. Therefore, targeting distinct STAT5-mediated survival signals, for example, bcl-2/bcl-X(L) and AKT/mTOR may be an effective therapeutic approach for human myeloproliferative neoplasms.
信号转导子和转录激活子 5（STAT5）是正常造血的关键转录因子，其持续激活与血液系统恶性肿瘤有关。STAT5 的一种持续激活的突变体（STAT5a[S711F]）与髓系白血病中的 Grb2 相关结合蛋白 2（Gab2）相关，并通过 AKT 激活促进体外生长。在这里，我们通过逆转录病毒转导表达 STAT5a[S711F]的野生型或 Gab2（-/-）小鼠骨髓细胞，并将其移植到照射的受体小鼠中，以测试体内骨髓增生性疾病模型。为了靶向 Gab2 非依赖性 AKT/mTOR 激活，我们分别用雷帕霉素处理野生型小鼠。在任何一种情况下，缺乏 Gab2 或用雷帕霉素治疗的小鼠均表现出髓样增生减弱，生存时间略有改善，但效果非细胞毒性且可逆转。为了改进这种方法，我们将雷帕霉素体外靶向 STAT5 介导的 AKT/mTOR 与使用 ABT-737 抑制 STAT5 的直接靶基因 bcl-2 和 bcl-X（L）结合使用。在表达 STAT5a[S711F]、TEL-JAK2 或 BCR-ABL 的小鼠 BaF3 细胞以及相对单一药物耐药的人 BCR-ABL 阳性 K562 细胞系中，观察到这两种药物均具有显著的协同作用。因此，靶向不同的 STAT5 介导的存活信号，例如 bcl-2/bcl-X（L）和 AKT/mTOR，可能是治疗人类骨髓增生性肿瘤的有效方法。
