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: 7743435
• 负责人: KYOKO HAYAKAWA
• 金额: $ 36.21万
• 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/7743435
• 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; 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; Lymphoblastic Leukemia; 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; Stem cells; System; T-Cell Leukemia; Testing; Tissues; Transgenes; Transgenic Organisms; Uncertainty; United States; Up-Regulation; Western Europe; Work; adult leukemia; aged; autoreactive B cell; cell growth; crosslink; design; experience; leukemia; leukemia/lymphoma; leukemogenesis; macrophage; mouse model; novel; outcome forecast; overexpression; public health relevance; research study; thymocyte

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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. A long-standing speculation proposes an autoantigen mediated mechanism for B CLL development. Our autoreactive CD5+ B cell mouse model system allows a detailed investigation of CLL development potential within tissues from early to late stage, and directly tests role of self-antigen, work not possible in humans. Elucidating the mechanism of CLL development in mice will be critically important both for prognosis and for designing rational therapies for dysregulated B cell expansions that can lead to aggressive cancer.

描述（由申请人提供）：人类B CLL（B细胞慢性淋巴细胞白血病）是一种在老年人群中发生的CD 5 + B细胞缓慢蓄积性疾病，占美国和西欧成人白血病病例的三分之一。虽然被认为是一种无痛性疾病，但有广泛的临床病程。由于缺乏关键细胞遗传学异常的鉴定以及其细胞起源和发病机制的不确定性，CLL的精确定义一直很困难。长期以来的推测是，由于特定IG VH家族基因的反复使用，抗原介导的BCR信号传导在B CLL发展中起重要作用。然而，这种假定的抗原驱动机制可以在白血病发生之前的不同阶段、在对失调敏感的B细胞池的建立期间和/或在白血病起始/进展的点处起作用。我们以前证明，自身抗原介导的BCR信号强度和质量依赖性CD 5诱导发生在自身反应性B细胞使用BCR转基因（Tg）小鼠系。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小鼠系提供了一个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）基因在B细胞中作为转基因的组成型过表达导致老年小鼠中发生CD 5 + B淋巴瘤/白血病，其表型类似于人B CLL，发生率高.通过将这种TCL 1 Tg引入我们的几种自身反应性BCR小鼠模型中，有或没有抗原，我们建议研究自身抗原暴露的重要性，B细胞起源，以及进行性B细胞白血病发生的机制。这项工作的一个重点是评估CD 5+自身反应性B细胞群，B1，建立了自身抗原暴露的积极选择的结果，在这个CLL模型的作用。虽然这些B细胞通常生长停滞在G 0/G1期，但我们的初步数据提供了当TCL 1过表达时其淋巴瘤/白血病发生潜力的证据。该系统允许从早期到晚期白血病发生的组织中淋巴瘤发育潜力的详细调查，这是在人类中不可能进行的研究。公共卫生相关性：人类B CLL（B细胞慢性淋巴细胞白血病）是一种在老年人群中发展的CD 5 + B细胞的缓慢累积性疾病，占美国和西欧成人白血病病例的三分之一。长期以来的推测提出了自身抗原介导的B CLL发展机制。我们的自身反应性CD 5 + B细胞小鼠模型系统允许详细研究组织内从早期到晚期的CLL发展潜力，并直接测试自身抗原的作用，这在人类中是不可能的。阐明小鼠中CLL发展的机制对于预后和设计可导致侵袭性癌症的失调B细胞扩增的合理疗法都至关重要。