Origin of CD5+ B cell Lymphoma/Leukemia in Mice

小鼠 CD5 B 细胞淋巴瘤/白血病的起源

• 批准号: 8204966
• 负责人: KYOKO HAYAKAWA
• 金额: $ 35.12万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204966
• 关键词: Accounting; Age; Antigen Receptors; Antigens; Autoantibodies; Autoantigens; B-Cell Development; B-Cell Lymphomas; B-Lymphocyte Subsets; B-Lymphocytes; Biological Models; Cells; Characteristics; Chromosome abnormality; Chronic Lymphocytic Leukemia; Clinical; Complement Activation; Cytokeratin 8; Data; Development; Disease; Elderly; Gene Family; Generations; Genes; Growth; Human; Immunoglobulin M; Incidence; Indolent; Investigation; Keratin; Lead; Life; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Mus; Outcome; Pathogenesis; Phenotype; Play; Population; Predisposition; Production; Public Health; Receptor Signaling; Receptors, Antigen, B-Cell; Recurrence; Role; Staging; System; T-Cell Leukemia; Testing; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Uncertainty; United States; Up-Regulation; Western Europe; Work; adult leukemia; aged; autoreactive B cell; cell growth; crosslink; design; experience; leukemia; leukemia/lymphoma; leukemic stem cell; leukemogenesis; macrophage; mouse model; novel; outcome forecast; overexpression; research study; thymocyte

Summary B CLL (B cell chronic lymphocytic leukemia) in humans is a slow accumulative disease of CD5+ B cells that develops in the elderly population, accounting for a third of adult leukemia cases in the United States and Western Europe. Although considered an indolent disease, there is a wide-ranging clinical course. Precise definition of CLL has been difficult due to lack of identification of key cytogenetic abnormalities and uncertainty over its cellular origins and pathogenesis. A long-standing speculation is that antigen-mediated BCR signaling plays a significant role in B CLL development, due to recurrent usage of particular Ig VH family genes. However, such a presumed antigen-driven mechanism could operate at different stages prior to leukemogenesis, during establishment of a B cell pool susceptible to dysregulation, and/or at the point of leukemic initiation/progression. We previously demonstrated that self-antigen mediated BCR signal strength- and quality-dependent CD5 induction occurs in autoreactive B cells using a BCR transgenic (Tg) mouse line. Therefore, CD5+ B CLL may originate from BCR crosslinking-experienced autoreactive B cells. Our autoreactive BCR Tg mouse lines provide a powerful model system to test this possibility. In mice, overexpression of the human TCL1 (T- cell leukemia/lymphoma-1) gene constitutively in B cells as a transgene results in CD5+ B lymphoma/leukemia development in aged mice, with a phenotype resembling human B CLL, at high incidence. By introducing this TCL1Tg into several of our autoreactive BCR mouse models, with or without antigen, we propose to investigate the importance of self-antigen exposure, B cell origin, and the mechanism of progressive B cell leukemogenesis. A focus of this work is to assess the role of the CD5+ autoreactive B cell population, B1, established by self-antigen exposure as an outcome of positive selection, in this CLL model. Although these B cells are normally growth-arrested at the G0/G1 stage, our preliminary data provided evidence for their lymphoma/leukemogenesis potential when TCL1 is overexpressed. This system allows a detailed investigation of lymphoma developmental potential in tissues from early to late stage leukemogenesis, a study not possible in humans.

总结 人类B CLL（B细胞慢性淋巴细胞白血病）是一种CD 5+的缓慢累积性疾病 B细胞在老年人中发展，占成年白血病病例的三分之一， 美国和西欧。虽然被认为是一种无痛性疾病， 广泛的临床过程。CLL的精确定义由于缺乏 确定关键的细胞遗传学异常及其细胞起源的不确定性， 发病机制一个长期存在的猜测是，抗原介导的BCR信号转导在细胞凋亡中起着重要作用。 在B CLL发展中的重要作用，这是由于特定IG VH家族基因的反复使用。 然而，这种假定的抗原驱动机制可以在免疫前的不同阶段起作用。 白血病发生，在建立对失调敏感的B细胞库期间，和/或 白血病开始/进展的点。我们之前证明了自体抗原 在自身反应性B细胞中发生介导的BCR信号强度和质量依赖性CD 5诱导 使用BCR转基因（Tg）小鼠系的细胞。因此，CD 5 + B CLL可能起源于BCR 交联经历的自身反应性B细胞。我们的自身反应性BCR Tg小鼠系提供了 强大的模型系统来测试这种可能性。在小鼠中，人TCL 1（T- 细胞白血病/淋巴瘤-1）基因作为转基因组成型地存在于B细胞中导致CD 5 + B 淋巴瘤/白血病在老年小鼠中的发展，具有类似于人B CLL的表型， 高发病率。通过将这种TCL 1 Tg引入我们的几种自身反应性BCR小鼠， 模型，有或没有抗原，我们建议调查的重要性，自我抗原 暴露、B细胞起源和进行性B细胞白血病发生机制。的焦点 这项工作是为了评估CD 5+自身反应性B细胞群B1的作用， 自身抗原暴露作为阳性选择的结果。虽然这些B 细胞通常生长停滞在G 0/G1期，我们的初步数据提供了证据， 当TCL 1过表达时，它们具有淋巴瘤/白血病发生的潜力。该系统允许 淋巴瘤从早期到晚期的组织发育潜力的详细研究 白血病的发生，这是一项不可能在人类身上进行的研究。