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Carcinogenesis Advance Access originally published online on May 2, 2008
Carcinogenesis 2008 29(9):1717-1724; doi:10.1093/carcin/bgn098
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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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,*

1 Department of Internal Medicine, Texas Tech University Health Sciences Center, 1400 Wallace Boulevard, Amarillo, TX 79106, USA
2 Stem Cell Transplant Program, Texas Tech University Health Sciences Center, 1400 Wallace Boulevard, Amarillo, TX 79106, USA
3 Institute of Clinical Molecular Biology, People's Hospital, Peking University, Beijing 100044, People's Republic of China
4 Division of Medical Oncology, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80010, USA

* To whom correspondence should be addressed. Tel: +1 806 354 5719; Fax: +1 806 354 5669; Email: zonghan.dai{at}ttuhsc.edu

Abl interactor (Abi) 1 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 short hairpin RNA attenuated the Bcr-Abl-induced abnormal actin remodeling, membrane-type 1 metalloproteinase clustering and inhibited cell adhesion and migration on fibronectin-coated surfaces. Although the knock down 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 non obese diabetic (NOD)/ severe combined immuno-deficiency (SCID) mice. Remarkably, the knock down 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 knock down 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.

Abbreviations: Abi, Abl interactor; F-actin, filament actin; FBS, fetal bovine serum; MT1-MMP, membrane-type 1 metalloproteinase; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; shRNA, short hairpin RNA; WAVE, WASP-family verprolin-homologous

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


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