Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.
Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, P.O.Box 700, 00290, Helsinki, Finland.
Leukemia. 2019 Jul;33(7):1583-1597. doi: 10.1038/s41375-018-0369-5. Epub 2019 Jan 24.
Deregulation of the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is found in cancer with STAT5A/B controlling leukemic cell survival and disease progression. As mutations in STAT5B, but not STAT5A, have been frequently described in hematopoietic tumors, we used BCR/ABL as model systems to investigate the contribution of STAT5A or STAT5B for leukemogenesis. The absence of STAT5A decreased cell survival and colony formation. Even more drastic effects were observed in the absence of STAT5B. STAT5B-deficient cells formed BCR/ABL colonies or stable cell lines at low frequency. The rarely evolving Stat5b cell lines expressed enhanced levels of BCR/ABL oncoprotein compared to wild-type cells. In line, Stat5b leukemic cells induced leukemia with a significantly prolonged disease onset, whereas Stat5a cells rapidly caused a fatal disease superimposable to wild-type cells. RNA-sequencing (RNA-seq) profiling revealed a marked enhancement of interferon (IFN)-α and IFN-γ signatures in Stat5b cells. Inhibition of IFN responses rescued BCR/ABL colony formation of Stat5b-deficient cells. A downregulated IFN response was also observed in patients suffering from leukemia carrying STAT5B mutations. Our data define STAT5B as major STAT5 isoform driving BCR/ABL leukemia. STAT5B enables transformation by suppressing IFN-α/γ, thereby facilitating leukemogenesis. Our findings might help explain the high frequency of STAT5B mutations in hematopoietic tumors.
Janus 激酶/信号转导子和转录激活子（JAK/STAT）信号通路的失调存在于癌症中，STAT5A/B 控制白血病细胞的存活和疾病进展。由于 STAT5B 而不是 STAT5A 的突变经常在造血肿瘤中被描述，我们使用 BCR/ABL 作为模型系统来研究 STAT5A 或 STAT5B 对白血病发生的贡献。STAT5A 的缺失降低了细胞存活和集落形成。在缺乏 STAT5B 的情况下观察到更为剧烈的影响。STAT5B 缺陷细胞以低频率形成 BCR/ABL 集落或稳定的细胞系。很少进化的 Stat5b 细胞系表达的 BCR/ABL 癌蛋白水平比野生型细胞高。与此一致，Stat5b 白血病细胞诱导白血病的发病时间明显延长，而 Stat5a 细胞则迅速导致与野生型细胞相似的致命疾病。RNA 测序（RNA-seq）分析显示 Stat5b 细胞中干扰素（IFN）-α和 IFN-γ 特征明显增强。抑制 IFN 反应挽救了 Stat5b 缺陷细胞的 BCR/ABL 集落形成。在患有携带 STAT5B 突变的白血病的患者中也观察到 IFN 反应下调。我们的数据将 STAT5B 定义为驱动 BCR/ABL 白血病的主要 STAT5 同工型。STAT5B 通过抑制 IFN-α/γ 来实现转化，从而促进白血病发生。我们的发现可能有助于解释 STAT5B 突变在造血肿瘤中的高频率。
