Haematologica. 2013 Nov;98(11):1748-52. doi: 10.3324/haematol.2013.085068. Epub 2013 Jul 19.
STAT3 protein phosphorylation is a frequent event in various hematologic malignancies and solid tumors. Acquired STAT3 mutations have been recently identified in 40% of patients with T-cell large granular lymphocytic leukemia, a rare T-cell disorder. In this study, we investigated the mutational status of STAT3 in a large series of patients with lymphoid and myeloid diseases. STAT3 mutations were identified in 1.6% (4 of 258) of patients with T-cell neoplasms, in 2.5% (2 of 79) of patients with diffuse large B-cell lymphoma but in no other B-cell lymphoma patients (0 of 104) or patients with myeloid malignancies (0 of 96). Functional in vitro assays indicated that the STAT3Y640F mutation leads to a constitutive phosphorylation of the protein. STA21, a STAT3 small molecule inhibitor, inhibited the proliferation of two distinct STAT3 mutated cell lines. Using a mouse bone marrow transplantation assay, we observed that STAT3Y640F expression leads to the development of myeloproliferative neoplasms with expansion of either myeloid cells or megakaryocytes. Together, these data indicate that the STAT3Y640F mutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies.
STAT3 蛋白磷酸化是各种血液恶性肿瘤和实体瘤中的常见事件。最近在 40%的 T 细胞大颗粒淋巴细胞白血病患者中发现了获得性 STAT3 突变，这是一种罕见的 T 细胞疾病。在这项研究中，我们研究了 STAT3 在一系列淋巴和髓系疾病患者中的突变状态。STAT3 突变在 258 例 T 细胞肿瘤患者中占 1.6%（4 例），在 79 例弥漫性大 B 细胞淋巴瘤患者中占 2.5%（2 例），但在其他 B 细胞淋巴瘤患者（0 例）或髓系恶性肿瘤患者（0 例）中均未发现。体外功能测定表明，STAT3Y640F 突变导致蛋白的持续磷酸化。STAT3 小分子抑制剂 STA21 抑制了两种不同的 STAT3 突变细胞系的增殖。使用小鼠骨髓移植模型，我们观察到 STAT3Y640F 表达导致骨髓增生性肿瘤的发生，髓系细胞或巨核细胞的扩增。总之，这些数据表明 STAT3Y640F 突变导致 STAT3 的持续激活，在体内诱导恶性造血，并可能成为某些淋巴恶性肿瘤的新治疗靶点。
