STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model
STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model
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DOI：
10.3324/haematol.2013.085068
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发表时间：
2013-11-01
期刊：
影响因子：
10.1
通讯作者：
Mercher, Thomas
中科院分区：
文献类型：
--
作者：
Couronne, Lucile;Scourzic, Laurianne;Mercher, Thomas
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（一种罕见的 T 细胞疾病）患者中发现了获得性 STAT3 突变。在这项研究中，我们调查了一系列淋巴和骨髓疾病患者的 STAT3 突变状态。在 1.6%（258 名中的 4 名）T 细胞肿瘤患者、2.5%（79 名中的 2 名）弥漫性大 B 细胞淋巴瘤患者中发现了 STAT3 突变，但在其他 B 细胞淋巴瘤患者（104 名中的 0 名）或骨髓恶性肿瘤患者（96 名中的 0 名）中没有发现 STAT3 突变。功能性体外测定表明 STAT3Y640F 突变导致蛋白质的组成型磷酸化。 STA21 是一种 STAT3 小分子抑制剂，可抑制两种不同 STAT3 突变细胞系的增殖。使用小鼠骨髓移植测定，我们观察到 STAT3Y640F 表达导致骨髓增殖性肿瘤的发展，伴有骨髓细胞或巨核细胞的扩张。总之，这些数据表明 STAT3Y640F 突变导致 STAT3 的组成型激活，诱导体内恶性造血，并可能代表一些淋巴恶性肿瘤的新治疗靶点。
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.