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Carcinogenesis Advance Access published online on May 2, 2008
Carcinogenesis, doi:10.1093/carcin/bgn098
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Abi1 Gene Silencing by Short Hairpin RNA Impairs Bcr-Abl-Induced Cell Adhesion and Migration in vitro and Leukemogenesis in vivo

Weidong Yu1,3, Xiaolin Sun1, Nancy Clough4, Everardo Cobos1,2, Yunxia Tao1 and Zonghan Dai1,2,5

1 Department of Internal Medicine
2 Stem Cell Transplant Program, Texas Tech University Health Sciences Center, Amarillo, Texas, U.S.A
3 Institute of Clinical Molecular Biology, People's Hospital, Peking University, Beijing, People's Republic of China
4 Division of Medical Oncology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado, U.S.A

5 Correspondence author: Zonghan Dai, Ph.D., Department of Internal Medicine, 1400 Wallace Blvd., Amarillo, TX 79106, Tel: 806-354-5719, Fax: 806-354-5669, E-mail: Zonghan.dai{at}ttuhsc.edu

Abi1 was first identified as the downstream target of Abl tyrosine kinases and was found to be dysregulated in leukemic cells expressing oncogenic Bcr-Abl and v-Abl. Although the accumulating evidence supports a role of Abi1 in actin cytoskeleton remodeling and growth factor/receptor signaling, it is not clear how it contributes to Bcr-Abl-induced leukemogenesis. We show here that Abi1 gene silencing by shRNA attenuated the Bcr-Abl-induced abnormal actin remodeling, MT1-MMP clustering and inhibited cell adhesion and migration on fibronectin-coated surfaces. Although the knockdown of Abi1 expression did not affect growth factor independent growth of Bcr-Abl-transformed Ba/F3 cells in vitro, it impeded competitive expansion of these cells in NOD/SCID mice. Remarkably, the knockdown of Abi1 expression in Bcr-Abl-transformed Ba/F3 cells impaired the leukemogenic potential of these cells in NOD/SCID mice. Abi1 contributes to Bcr-Abl-induced leukemogenesis in part through Src family kinases, as the knockdown of Abi1 expression attenuates Bcr-Abl-stimulated activation of Lyn. Together, these data provide for the first time the direct evidence that supports a critical role of Abi1 pathway in the pathogenesis of Bcr-Abl-induced leukemia

Key Words: Abi1 • Bcr-Abl • leukemogenesis • actin cytoskeleton • cell adhesion and migration

Received December 2, 2007; revised April 3, 2008; accepted April 8, 2008.


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