Origin of CD5+ B cell Lymphoma/Leukemia in Mice

摘要 人类B细胞慢性淋巴细胞白血病是一种CD5+慢性蓄积性疾病 B细胞在老年人群中发展，占#年成人白血病病例的三分之一 美国和西欧。虽然被认为是一种惰性疾病，但有一种 广泛的临床课程。CLL的准确定义一直很困难，因为缺乏 确定关键的细胞遗传学异常及其细胞起源和不确定性 发病机制。长期以来的猜测是，抗原介导的bcr信号在 由于特定的Ig VH家族基因的反复使用，在B CLL的发育中起着重要的作用。 然而，这种假定的抗原驱动的机制可以在不同的阶段运行，在 白血病发生，在建立易受调节失调的B细胞池期间，和/或 白血病发生/发展的时间点。我们之前证明了自身抗原 自身反应性B中介导的BCR信号强度和质量依赖的CD5诱导 使用BCR转基因(TG)小鼠系的细胞。因此，CD5+B CLL可能起源于BCR 交联型--经历自体反应的B细胞。我们的自动反应型BCR TG小鼠品系提供了 强大的模型系统来测试这一可能性。在小鼠中过表达人TCL1(T- 细胞白血病/淋巴瘤-1)基因在B细胞中构成转基因导致CD5+B 淋巴瘤/白血病在老年小鼠中的发展，其表型类似于人类B-CLL，在 发病率高。通过将该TCL1Tg引入我们的几个自身反应性BCR小鼠 无论有无抗原，我们都建议研究自身抗原的重要性。 暴露、B细胞来源和进行性B细胞白血病的发生机制。一个焦点 这项工作是为了评估CD5+自身反应性B细胞群体B1的作用，该B细胞群体由 在这个CLL模型中，自身抗原暴露是阳性选择的结果。虽然这些B 细胞通常生长停滞在G0/G1期，我们的初步数据提供了证据 当TCL1过表达时，它们的淋巴瘤/白血病发生能力。这个系统允许 淋巴瘤从早期到晚期在组织中发展潜力的详细调查 白血病发生，这项研究在人类上是不可能的。

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.