Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
J Clin Invest. 2018 Jan 2;128(1):387-401. doi: 10.1172/JCI94509. Epub 2017 Dec 4.
STAT5B is often mutated in hematopoietic malignancies. The most frequent STAT5B mutation, Asp642His (N642H), has been found in over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human STAT5B or STAT5BN642H in the hematopoietic compartment. While STAT5B-expressing mice lacked a hematopoietic phenotype, the STAT5BN642H-expressing mice rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8+ lymphoma or leukemia, indicating that the STAT5BN642H mutation drives cancer development. Persistent and enhanced levels of STAT5BN642H tyrosine phosphorylation in transformed CD8+ T cells led to profound changes in gene expression that were accompanied by alterations in DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes were enriched in STAT5BN642H-expressing CD8+ T cells, which were exquisitely sensitive to JAK and Aurora kinase inhibitors. Together, our data suggest that JAK and Aurora kinase inhibitors should be further explored as potential therapeutics for lymphoma and leukemia patients with the STAT5BN642H mutation who respond poorly to conventional chemotherapy.
STAT5B 常发生突变，进而导致血液系统恶性肿瘤。最常见的 STAT5B 突变，即 Asp642His（N642H），已在超过 90 例白血病和淋巴瘤患者中被发现。在此，我们利用 Vav1 启动子，构建了在造血细胞中表达人 STAT5B 或 STAT5BN642H 的转基因小鼠模型。虽然表达 STAT5B 的小鼠缺乏造血表型，但表达 STAT5BN642H 的小鼠迅速发展为 T 细胞肿瘤。肿瘤表现为可移植的 CD8+淋巴瘤或白血病，表明 STAT5BN642H 突变驱动癌症的发展。转化的 CD8+T 细胞中 STAT5BN642H 酪氨酸磷酸化水平持续增强，导致基因表达发生深刻变化，同时潜在的组蛋白甲基转移酶 EZH2 结合位点的 DNA 甲基化也发生改变。Aurora 激酶基因在表达 STAT5BN642H 的 CD8+T 细胞中富集，这些细胞对 JAK 和 Aurora 激酶抑制剂极其敏感。综上，我们的数据表明，JAK 和 Aurora 激酶抑制剂应作为 STAT5BN642H 突变、对常规化疗反应不佳的淋巴瘤和白血病患者的潜在治疗药物进一步研究。
