BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia
BCR-ABL1 mediates up-regulation of Fyn in chronic myelogenous leukemia
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DOI：
10.1182/blood-2007-05-091769
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发表时间：
2008-03-01
期刊：
影响因子：
20.3
通讯作者：
Chandra, Joya
中科院分区：
文献类型：
--
作者：
Ban, Kechen;Gao, Yin;Chandra, Joya
慢性骨髓性白血病（CML）总是进展到原细胞危象，这是该疾病最增生的阶段。BCR-ABL1癌基因通过磷酸化多种底物（包括各种Src家族成员）来刺激生长和生存途径。在这里，我们描述了BCR-ABL1对普遍表达的Src激酶Fyn的上调，而不是激活。在组织芯片检测中，Fyn的表达在CML细胞危象期明显高于慢性期。体外和体内过表达BCR-ABL1的细胞显示Fyn蛋白和mRNA的上调。用shRNA敲低Fyn可减缓白血病细胞生长，抑制克隆原性，导致对伊马替尼的敏感性增加，表明Fyn介导CML细胞增殖。在严重联合免疫缺陷（SCID）小鼠中注射表达Fyn shrna的细胞，髓源性细胞数量下降50%，白血病死亡延迟。综上所述，这些结果鼓励了针对Fyn表达的治疗方法的发展。
Chronic myelogenous leukemia (CML) invariably progresses to blast crisis, which represents the most proliferative phase of the disease. The BCR-ABL1 oncogene stimulates growth and survival pathways by phosphorylating numerous substrates, including various Src family members. Here we describe up-regulation, in contrast to activation, of the ubiquitously expressed Src kinase, Fyn, by BCR-ABL1. In a tissue microarray, Fyn expression was significantly increased in CML blast crisis compared with chronic phase. Cells overexpressing BCR-ABL1 in vitro and in vivo display an up-regulation of Fyn protein and mRNA. Knockdown of Fyn with shRNA slows leukemia cell growth, inhibits clonogenicity, and leads to increased sensitivity to imatinib, indicating that Fyn mediates CML cell proliferation. In severe combined immunodeficient (SCID) mice injected with Fyn shRNA-expressing cells, myeloid-derived cell numbers dropped by 50% and death from leukemia was delayed. Taken together, these results encourage the development of therapies targeting Fyn expression.