Dysregulation of Micrornas Involved In HTLV-Associated Adult T-Cell Lymphoma

Abstract 3122

Adult T-cell leukemia/lymphoma (ATL) is an aggressive, fatal malignancy of CD4+ T cells that is etiologically associated with infection by human T-cell leukemia virus-type. ATL has been classified into four main subtypes, indolent smoldering, chronic forms, acute and lymphomatous forms. Most individuals in the chronic stage of ATL eventually undergo progression to a highly aggressive acute stage. Compelling evidence supports a pivotal role for altered tumor suppressor genes involved in leukemogenesis and lymphomagenesis of ATL as well as progression of the disease from the chronic/smoldering to the acute/lymphomatous type. Further investigations are needed as to how the alteration of cell cycle regulatory genes are involved in the aberrant growth of HTLV-infected T cells. The emerging role of microRNAs in tumor development and viral infection has prompted investigations on the role of microRNA in ATL pathogenesis and progression. We therefore performed microRNA microarrays on 16 lymphomatous tissues of ATL patients and normal CD4 lymphocytes of 5 healthy donors. After normalization, we identified a set of aberrantly expressed miRNAs in ATL lymphoma samples when compared with control CD4 lymphocytes including 49 upregulated microRNAs and 89 downregulated microRNAs. MiR-150, miR-24, miR-221, miR-222, miR-142-5p, miR-92b, miR-93, miR-181a, miR-103, miR-107 stands out as highly elevated miRNAs in ATL samples while miR-30b, miR-34a, miR-20b, miR-196b, miR-361-5p, miR-520b/e are found downregulated in ATLL samples. Using gain-and-loss experimentations, we demonstrated miR-181a overexpression decreases, whereas miR-181a inhibition increases a proapoptotic protein, Bim, levels by directly targeting Bim. Furthermore computational analysis, and previous studies revealed that that miR-214, miR-22, miR-93 increased AKT activity by repressing PTEN expression, and miR-221/222 and miR-93 promoted cell proliferation through inhibition of CDKN1B (p27). Overall, this study demonstrated a distinct set of miRNAs that are known to be critical in cellular transformation, representing a novel molecular mechanism and potential therapeutic targets in ATL lymphoma.