Abi1 gene silencing by short hairpin RNA impairs Bcr-Abl-induced cell adhesion and migration in vitro and leukemogenesis in vivo

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Carcinogenesis 2008 29(9):1717-1724; doi:10.1093/carcin/bgn098

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, 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@...

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.