文章：

敲除STAT5能够阻断TEL-SYK诱导的小鼠APMF型白血病，该疾病伴随骨髓纤维化和骨髓增生异常

Depletion of STAT5 blocks TEL–SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice

原文发布日期：2014-08-22

DOI: 10.1038/bcj.2014.53

类型: Original Article

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英文摘要：

The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYKwt, TEL–SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYKwt enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK–SYK caused lethal T-cell lymphomas and the cytoplasmic TEL–SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL–SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL–SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL–SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases.

摘要翻译： 

脾酪氨酸激酶（SYK）被确定为广泛血液恶性肿瘤的致癌驱动因子。对三种含SYK致癌基因（SYKwt、TEL-SYK和IL-2诱导性T细胞激酶（ITK）-SYK）的体内比较研究显示，它们均引起全身性骨髓扩张并形成三种不同的血液系统（前）疾病状态。SYKwt增强了髓系和T细胞区室，但未引发白血病/淋巴瘤；ITK-SYK导致致死性T细胞淋巴瘤；而胞质型TEL-SYK融合基因则诱发伴有骨髓纤维化的急性全骨髓增生症——即急性髓系白血病（AML），其特征包括高达50%的未成熟巨核母细胞浸润骨髓、脾脏和肝脏，兼具骨髓增生性肿瘤特征（骨髓纤维化和粒细胞扩增）及骨髓增生异常综合征标志（巨核细胞和红系细胞发育异常）。LKS细胞数量减少，所有亚群（LT/ST/MPP）增殖速率均下降。对患病TEL-SYK小鼠进行SYK抑制剂（R788）治疗，可降低白细胞计数、减轻脾脏和肝脏浸润、提高红细胞比容并延长生存时间，但未能显著改善骨髓纤维化。研究证实Stat5是TEL-SYK在体外和体内的主要下游介质。值得注意的是，体内靶向敲除Stat5能完全阻断TEL-SYK诱导的AML和骨髓纤维化进程，证实Stat5是SYK诱导转化的关键驱动因子。本实验揭示了SYK在AML和骨髓纤维化中的重要作用，并证明SYK与STAT5抑制剂是治疗这类疾病的有效方案。

原文链接：

Depletion of STAT5 blocks TEL–SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice