Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC.
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Blood Cancer J. 2017 Jul 28;7(7):e588. doi: 10.1038/bcj.2017.67.
Suppressor of cytokine signaling 1 (SOCS1) protein, which encodes a member of signal transducers and activators of transcription-induced inhibitors, takes part in a negative regulation of cytokine signaling. The mechanism of SOCS1 in tumor carcinogenesis is complex and there have been no studies concerning the clinic-biologic implication of SOCS1 expression in acute myeloid leukemia (AML). Here, we first identified that higher bone marrow (BM) SOCS1 expression was closely associated with older age, FLT3-ITD, NPM1 and DNMT3A mutations, but negatively correlated with CEBPA mutation in patients with de novo AML. Compared to patients with lower SOCS1 expression, those with higher expression had lower complete remission rates and shorter overall survival. Further, higher expression of SOCS1 in the BM was an independent unfavorable prognostic factor irrespective of age, white blood cell, cytogenetics and gene mutations. Next, we generated zebrafish model overexpressing SOCS1 by spi1 promoter, which showed kidney marrow from adult SOCS1 zebrafish had increased myelopoiesis, myeloid progenitors and the kidney or spleen structure were effaced and distorted, mimicking leukemia phenotype. The SOCS1/FLT3-ITD double transgenic fish could further facilitate the leukemic process. The results indicate SOCS1 plays an important role in AML and its higher expression serves as a new biomarker to risk-stratify AML patients.
细胞因子信号转导抑制因子 1（SOCS1）蛋白是信号转导和转录激活因子诱导抑制剂的成员之一，参与细胞因子信号的负调控。SOCS1 在肿瘤发生中的作用机制复杂，目前尚无关于 SOCS1 在急性髓系白血病（AML）中的表达与临床生物学意义的研究。在这里，我们首先确定骨髓（BM）中 SOCS1 表达较高与年龄较大、FLT3-ITD、NPM1 和 DNMT3A 突变密切相关，但与初诊 AML 患者的 CEBPA 突变呈负相关。与 SOCS1 表达较低的患者相比，SOCS1 表达较高的患者完全缓解率较低，总生存期较短。此外，BM 中 SOCS1 的高表达是独立的不利预后因素，与年龄、白细胞计数、细胞遗传学和基因突变无关。接下来，我们通过 spi1 启动子生成了过表达 SOCS1 的斑马鱼模型，该模型显示成年 SOCS1 斑马鱼的骨髓中有更多的髓样细胞生成、髓样祖细胞增多，肾脏或脾脏结构消失和变形，模拟白血病表型。SOCS1/FLT3-ITD 双转基因鱼可进一步促进白血病进程。结果表明 SOCS1 在 AML 中发挥重要作用，其高表达可作为风险分层 AML 患者的新生物标志物。
