Interplay between Pax5 and Myc in B-lymphomagenesis

Pax5是B细胞分化的关键调节因子，是向B淋巴谱系定型所必需的。它的缺乏允许前B细胞容易采取其他命运。相反，在前B细胞中不能沉默Pax5被认为有助于肿瘤转化。例如，Pax5在淋巴浆细胞性淋巴瘤中过表达，这是由于染色体易位并置了Pax5和IgH基因座。在其他类型的非霍奇金病（弥漫性大细胞和伯基特淋巴瘤）中，Pax5通常与Myc（一种确认的癌基因）共表达沿着。然而，Pax5作为癌基因本身的作用尚未确定。为此，已经开发了一种模型系统，其中将p53缺失的骨髓细胞转导到 用表达Myc的逆转录病毒进行体内试验。在同源宿主中，这些细胞引起侵袭性Pax5阳性B细胞淋巴瘤。然而，从其衍生的一些细胞系自发地沉默Pax5并转化为髓样表型，经常丧失致瘤性。因此，Pax5的生理水平对于Myc诱导的肿瘤的B淋巴表型至关重要。此外，超生理水平的Pax5，通过逆转录病毒转导，发现大大提高Myc诱导的肿瘤细胞生长。在目前的建议中，逆转录病毒转导系统将用于阐明Pax5在淋巴瘤发生中的确切作用。将讨论三个重要问题。1. Pax5在限制Myc诱导的造血系统肿瘤为B淋巴瘤中的作用假设Myc转化的细胞是多能的。为了保持对淋巴谱系的定向并阻止髓样分化，它们需要Pax5，Pax5作为前髓样转录的拮抗剂 因子PU.1。2. Pax5在骨髓细胞中的转化潜力。假设至少在p53不存在的情况下，Pax5可以启动肿瘤生长并在肿瘤维持中取代Myc。3. Pax5沉默对B淋巴瘤发生的影响假设是肿瘤前B细胞中Pax5的失活将导致致瘤性的丧失或减弱。这些实验结果可以确定Pax5作为基因特异性治疗干预的有效靶点，这将使各种B细胞淋巴瘤患者受益。

Pax5 is a key regulator of B-cell differentiation, necessary for commitment to the B-lymphoid lineage. Its absence allows pro-B-cells to readily adopt other fates. Conversely, failure to silence Pax5 in pre-B-cells is thought to contribute to neoplastic transformation. For example, Pax5 is over-expressed in lymphoplasma-cytic lymphomas due to a chromosomal translocation juxtaposing pax5 and IgH loci. In other types of non-Hodgkin disease (diffuse large cell and Burkitt lymphomas), Pax5 is often co-expressed along with Myc, a confirmed oncogene. However, the role of Pax5 as an oncogene in its own right is yet to be established. To this end, a model system has been developed wherein p53-null bone marrow cells are transduced in vivo with retroviruses expressing Myc. In syngeneic hosts, these cells give rise to aggressive, Pax5-positive B-cell lymphomas. However, some cell lines derived therefrom spontaneously silence Pax5 and convert to a myeloid phenotype, with frequent loss of tumorigenicity. Thus, physiological levels of Pax5 are crucial for the B-lymphoid phenotype of Myc-induced neoplasms. Moreover, supraphysiological levels of Pax5, achieved via retroviral transduction, were found to greatly enhance Myc-induced tumor cell growth. In the current proposal, the retroviral transduction system will be used to elucidate the exact role of Pax5 in lymphomagenesis. Three important issues will be addressed. 1. The role of Pax5 in restricting Myc-induced hematopoietic neoplasms to B-lymphomas. The hypothesis is that Myc-transformed cells are multipotent. To remain committed to the lymphoid lineage and thwart myeloid differentiation, they require Pax5 which serves as an antagonist of the pro-myeloid transcription factor PU.1. 2. The transforming potential of Pax5 in bone marrow cells. The hypothesis is that at least in the absence of p53, Pax5 can initiate neoplastic growth and supplant Myc in tumor sustenance. 3. The consequences of Pax5 silencing for B-lymphomagenesis. The hypothesis is that inactivation of Pax5 in neoplastic pre-B cells will result in loss or attenuation of tumorigenicity. These experimental results may identify Pax5 as a valid target for gene-specific therapeutic interventions that would benefit patients with a variety of B-cell lymphomas.