Origin of CD5+ B cell Lymphoma/Leukemia in Mice

描述(申请人提供)：人类B细胞慢性淋巴细胞白血病(B细胞慢性淋巴细胞白血病)是一种慢性累积性疾病，CD5+B细胞在老年人群中发展，占美国和西欧成人白血病病例的三分之一。虽然被认为是一种惰性疾病，但有一个广泛的临床过程。由于缺乏对关键的细胞遗传学异常的识别，以及对其细胞起源和发病机制的不确定性，CLL的准确定义一直是困难的。长期以来的推测是，由于特定的Ig VH家族基因的反复使用，抗原介导的BCR信号在B CLL的发展中起着重要作用。然而，这种假定的抗原驱动机制可能在白血病发生前的不同阶段、在建立易受调节失调的B细胞库期间和/或在白血病开始/发展点起作用。我们先前使用BCR转基因(TG)小鼠系证明了自身抗原介导的BCR信号强度和质量依赖的CD5诱导发生在自身反应性B细胞中。因此，CD5+BCLL可能来源于BCR交联型自身反应性B细胞。我们的自动反应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TCL1(T细胞白血病/淋巴瘤-1)基因作为转基因在B细胞中结构性过表达，导致CD5+B淋巴瘤/白血病在老年小鼠中的发展，其表型类似于人B CLL，是一种高发疾病。通过将此TCL1Tg引入我们的几个有或没有抗原的自身反应性BCR小鼠模型中，我们建议研究自身抗原暴露的重要性、B细胞来源以及进行性B细胞白血病发生的机制。这项工作的一个重点是评估CD5+自身反应性B细胞群B1在这个CLL模型中的作用，该B细胞群是通过自身抗原暴露建立的，作为阳性选择的结果。虽然这些B细胞通常生长停滞在G0/G1期，但我们的初步数据提供了当TCL1过表达时它们发生淋巴瘤/白血病的可能性的证据。这一系统允许详细研究从白血病发生的早期到晚期组织中的淋巴瘤发展潜力，这是一项在人类中不可能进行的研究。公共卫生相关性：人类B细胞慢性淋巴细胞白血病(B细胞慢性淋巴细胞白血病)是一种CD5+B细胞慢性累积性疾病，在老年人群中发展，占美国和西欧成人白血病病例的三分之一。长期以来，一种推测认为B-CLL的发生是由自身抗原介导的。我们的自身反应性CD5+B细胞小鼠模型系统允许从早期到晚期详细研究组织内CLL的发展潜力，并直接测试自身抗原的作用，这在人类是不可能的。阐明小鼠CLL的发生机制对于预后和设计合理的治疗方法将是至关重要的，因为B细胞的异常扩张可能导致侵袭性癌症。

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.