Role of miR-124a in HTLV-I oncogenesis

描述(申请人提供)：人类T细胞白血病病毒1型(HTLV-I)是成人T细胞白血病(ATL)的病原体，ATL是一种侵袭性和致命性疾病，其特征是感染病毒的CD4+T细胞克隆性增殖。据估计，全球有2000万至3000万人感染了HTLV-I。ATL预后最差，急性期中位生存期为6-9个月，淋巴瘤期为10-12个月。总体而言，接受不同化疗或放疗方案治疗的ATLL患者的存活率有限，因为大多数患者复发后不久就会死于侵袭性肿瘤。HTLV-I肿瘤发生的分子基础尚不清楚。发病前的低发病率和长潜伏期表明，宿主感染细胞的遗传改变的积累是疾病进展所必需的。我们发现，在ATL细胞中，microRNA miR-124A通过其启动子的表观遗传沉默而特异性下调。在这项提案中，我们将进一步表征miR-124A在HTLV-I感染细胞的增殖和存活中的作用。然后，我们将研究miR-124A与HTLV-I转化细胞中其他解除调控的microRNA之间的潜在合作。由于miR-124A在许多人类癌症中表达下调，这一提议具有广泛影响的潜力。 公共卫生相关性：本申请建议研究HTLV-I感染细胞和成人T细胞白血病(ATL)(一种致命的淋巴增殖性疾病)中miR-124A发生表观遗传沉默的机制。由于在各种人类癌症中也观察到了类似的变化，我们的研究可能为人类癌症的治疗提供新的治疗靶点。

DESCRIPTION (provided by applicant): Human T-cell Leukemia Virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL), an aggressive and fatal disease characterized by a clonal expansion of virus-infected CD4+T cells. It is estimated that 20 to 30 million people worldwide are infected with HTLV-I. ATL has one of the poorest prognoses, with a median survival of 6-9 months in the acute phase and 10-12 months in the lymphoma phase. Overall, survival of ATLL patients treated with various chemotherapy or radiotherapy regimens is limited, as most patients relapse with aggressive tumors and succumb shortly thereafter. The molecular basis of HTLV-I oncogenesis is not well understood. The low incidence and long latency before the onset of the disease suggest that accumulation of genetic alterations of host infected cells is required for disease progression. We have found that microRNA miR-124a is specifically down-regulated through epigenetic silencing of its promoter in ATL cells. In this proposal, we will further characterize the role of miR-124a on the proliferation and survival of HTLV-I infected cells. We will then study the potential cooperation between miR-124a and other microRNA deregulated in HTLV-I transformed cells. Since miR-124a is down regulated in many human cancers, this proposal has the potential for broad implications. PUBLIC HEALTH RELEVANCE: This application proposes to investigate the mechanism by which epigenetic silencing of miR- 124a occurs in HTLV-I infected cells and adult T-cell leukemia (ATL), a fatal lymphoproliferative disease. Since similar changes are also observed in various human cancers, our studies may offer new therapeutic targets for the treatment of human cancers.