期刊
LEUKEMIA
卷 25, 期 2, 页码 305-312出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2010.257
关键词
chronic myelogenous leukemia; leukemia stem cells; signal transduction; gene transfer
资金
- NIH [R01 HL77847, R01CA095684]
- COHNMC Analytical Cytometry and Sequencing cores
Chronic myeloid leukemia (CML) results from the expression of the BCR/ABL oncogene in a primitive hematopoietic cell. However, BCR/ABL-activated signaling mechanisms are dependent on the cellular context in which it is expressed, and mechanisms underlying primitive human hematopoietic cell transformation by BCR-ABL are not well understood. Our previous studies have shown that BCR/ABL-Y177 has an essential role in Ras activation and human hematopoietic progenitor transformation in CML. The adapter protein growth factor receptor-binding protein-2 (Grb2) can bind phosphorylated BCR/ABL-Y177, induce Grb2-SoS complex formation and activate Ras signaling. We investigated the role of Grb2 in CML progenitor transformation by cotransducing human CD34+ cells with lentivirus vectors expressing short hairpin RNA to Grb2 and retrovirus vectors expressing BCR/ABL. We show that Grb2 knockdown significantly inhibits proliferation and survival of BCR-ABL-expressing CD34+ cells, but not control CD34+ cells. Grb2 knockdown reduced mitogen-activated protein kinase (MAPK) activity in BCR-ABL-expressing hematopoietic cells. We conclude that inhibition of Grb2 expression demonstrates an important role in BCR-ABL-mediated MAPK activation and transformation of primary human hematopoietic cells. These results support further investigation of downstream effectors of Grb2-mediated signals and targeting of Grb2 interactions in the treatment of CML. Leukemia (2011) 25, 305-312; doi:10.1038/leu.2010.257; published online 12 November 2010
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据