Role of miR155 in Leukemogenesis

miR155 在白血病发生中的作用

• 批准号: 8212584
• 负责人: CARLO M CROCE
• 金额: $ 30.11万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212584
• 关键词: 13q14; Acute Lymphocytic Leukemia; Antineoplastic Agents; Apoptosis; B-Cell Neoplasm; B-Lymphocytes; BCL2 gene; Birth; Burkitt Lymphoma; Cancer Etiology; Cell physiology; Chromosome Mapping; Chromosome abnormality; Chronic Lymphocytic Leukemia; Colon Carcinoma; DNA Sequence Rearrangement; Development; Down-Regulation; Enhancers; Family; Gene Chips; Gene Expression; Gene Expression Regulation; Genes; Genetic Translation; Health; Human; Immunoglobulins; Indolent; Liquid substance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of thyroid; MicroRNAs; Molecular Profiling; Mus; Nucleotides; Oncogenes; Oncogenic; Pathogenesis; Phenotype; Prevention; Prevention strategy; Process; Role; Small RNA; Solid; Solid Neoplasm; T-Cell and NK-Cell Neoplasm; Testing; Tissues; Transgenic Mice; Tumor Suppressor Genes; Up-Regulation; base; biological adaptation to stress; large cell Diffuse non-Hodgkin' s lymphoma; leukemogenesis; mRNA Transcript Degradation; malignant breast neoplasm; malignant stomach neoplasm; overexpression; prevent; tumorigenesis

DESCRIPTION (provided by applicant): Role of miR155 in Leukemogenesis Expression of microRNA genes is consistently altered in liquid and solid malignancies. We have shown that microRNA genes such as miR15 and miR16 function essentially as tumor suppressor genes in B cells and are deleted or underexpressed in chronic lymphocytic leukemia (CLL) with an indolent phenotype. We have also shown that miR15 and miR16 target the BCL2 oncogene. Thus decreased expression of miR-15 and miR-16 leads to BCL2 overexpression, contributing to malignant transformation. On the contrary, other microRNA genes are overexpressed in human malignancies: for example miR155 is overexpressed in aggressive CLLs, in a fraction of Burkitt's lymphomas, in ABC type of diffuse large B cell lymphoma and in several solid tumors. We intend to prove that miR155 is an oncogenic microRNA involved in human cancer and that inhibition of this microRNA can result in the prevention and treatment of miR155 driven malignancies. For this purpose, we have constructed transgenic mice in which we targeted overexpression of miR155 to pre B cells by using the immunoglobulin E5 enhancer. Analysis of these mice indicated the development of aggressive pre B cell neoplasms, signs of which are already detectable 3-4 weeks after birth. We propose: 1) to demonstrate that the overexpression of a single microRNA, miR155, can cause an aggressive malignancy; 2) to demonstrate the involvement of miR155 in human acute lymphoblastic leukemia, and 3) to demonstrate that miR155 antagomiRs can result in the prevention and regression of ALL in leukemic transgenic mice. Thus this study will provide the rationale for the development of a miR based strategy for the prevention and cure of cancers caused by microRNA deregulation. PUBLIC HEALTH RELEVANCE: We propose to investigate the role of a microRNA, miR155, in the pathogenesis of human cancer. This microRNA is overexpressed in several different human cancers. The study will rely on transgenic mice that overexpress this microRNA in their B cells. Since miR155 transgenic mice develop aggressive malignancies, we will test the hypothesis that by inhibiting the expression of this microRNA the malignancies will regress. This will provide the basis for the development of antimiR155 therapies in human cancer.

描述（由申请人提供）：miR155 在白血病发生中的作用 microRNA 基因的表达在液体和固体恶性肿瘤中持续改变。我们已经证明，诸如 miR15 和 miR16 等 microRNA 基因在 B 细胞中本质上起着抑癌基因的作用，并且在具有惰性表型的慢性淋巴细胞白血病 (CLL) 中被删除或表达不足。我们还表明 miR15 和 miR16 靶向 BCL2 癌基因。因此，miR-15 和 miR-16 表达降低导致 BCL2 过度表达，从而导致恶性转化。相反，其他 microRNA 基因在人类恶性肿瘤中过度表达：例如 miR155 在侵袭性 CLL、部分伯基特淋巴瘤、ABC 型弥漫性大 B 细胞淋巴瘤和几种实体瘤中过度表达。我们打算证明 miR155 是一种与人类癌症有关的致癌 microRNA，抑制这种 microRNA 可以预防和治疗 miR155 驱动的恶性肿瘤。为此，我们构建了转基因小鼠，其中我们使用免疫球蛋白 E5 增强子将 miR155 的过度表达靶向前 B 细胞。对这些小鼠的分析表明，它们出现了侵袭性前 B 细胞肿瘤，其迹象在出生后 3-4 周就可以检测到。我们建议：1）证明单个 microRNA miR155 的过度表达可以导致侵袭性恶性肿瘤； 2) 证明 miR155 参与人类急性淋巴细胞白血病，以及 3) 证明 miR155 antagomirs 可以预防和消退白血病转基因小鼠的 ALL。因此，这项研究将为开发基于 miR 的策略来预防和治疗由 microRNA 失调引起的癌症提供理论基础。公共健康相关性：我们建议研究 microRNA（miR155）在人类癌症发病机制中的作用。这种 microRNA 在几种不同的人类癌症中过度表达。该研究将依赖于在 B 细胞中过度表达这种 microRNA 的转基因小鼠。由于 miR155 转基因小鼠会发展出侵袭性恶性肿瘤，因此我们将测试以下假设：通过抑制这种 microRNA 的表达，恶性肿瘤将会消退。这将为人类癌症中抗miR155疗法的开发提供基础。