Evidence for an oncogenic role of AHI-1 in Sezary syndrome, a leukemic variant of human cutaneous T-cell lymphomas
| Autor: | Andrew P. Weng, X-J Li, Liang L. Zhou, M W Su, Ashley Ringrose, Youwen Zhou, M R Pittelkow, Emily Pang, Guoqing Sheng, A E-J Lin, Xiaoyan Jiang |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Skin Neoplasms T cell Blotting Western Genetic Vectors Mice SCID Lymphoma T-Cell Cell Line Mice Mice Inbred NOD Animals Humans Sezary Syndrome Medicine Autocrine signalling Sezary Cell Adaptor Proteins Signal Transducing DNA Primers Gene knockdown Base Sequence business.industry Cutaneous T-cell lymphoma Hematology medicine.disease Lymphoma Adaptor Proteins Vesicular Transport Leukemia Retroviridae medicine.anatomical_structure Oncology Immunology Cancer research Cytokines RNA Interference Stem cell business |
| Zdroj: | Leukemia. 20:1593-1601 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/sj.leu.2404321 |
| Popis: | 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 (TNFalpha) 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 TNFalpha 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|