1. ¹Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
2. ²Skin Oncology Group, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
3. ³Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
4. ⁴Department of Human Genetics, Emory University, Atlanta, GA, USA
5. ⁵Departments of Medicine, Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
6. ⁶Department of Dermatology, Mayo Clinic College of Medicine, Rochester, MN, USA
7. ⁷Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

Correspondence: Dr X Jiang, Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3. E-mail: xjiang@bccrc.ca

Received 4 December 2005; Revised 15 June 2006; Accepted 16 June 2006; Published online 13 July 2006.

Abstract

Ahi-1 (Abelson helper integration site 1) is a novel gene frequently activated by provirus insertional mutagenesis in murine leukemias and lymphomas. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in human leukemia cells, particularly in cutaneous T-cell lymphoma cell lines where increases in AHI-1 transcripts of 40-fold are seen. To test directly whether deregulated expression of AHI-1 contributes to their transformed properties, knockdown of AHI-1 expression in Hut78 cells, a cell line derived from a patient with Sezary syndrome (SS), was performed using retroviral-mediated RNA interference. Retroviral-mediated suppression specifically inhibited expression of AHI-1 and its isoforms in transduced cells by 80% and also reduced autocrine production of interleukin (IL)-2, IL-4 and tumor necrosis factor-alpha (TNF) by up to 85%. It further significantly reduced their growth factor independence in vitro and the ability to produce tumors in immunodeficient mice. Interestingly, aberrant expression of AHI-1, particularly truncated isoforms, was present in CD4⁺CD7^- Sezary cells from some patients with SS. Elevated expression of IL-2 and TNF was also found in these cells. These findings provide strong evidence of the oncogenic activity of AHI-1 in human leukemogenesis and demonstrate that its deregulation may contribute to the development of SS.