Interplay between Pax5 and Myc in B-lymphomagenesis

Pax5是B细胞分化的关键调节因子，对B淋巴系的承诺是必要的。它的缺失使得亲B细胞很容易接受其他的命运。相反，未能沉默前B细胞中的Pax5被认为是导致肿瘤转化的原因。例如，Pax5在淋巴浆细胞性淋巴瘤中过度表达，这是由于Pax5和IgH基因的染色体易位并列。在其他类型的非霍奇金病(弥漫性大细胞淋巴瘤和伯基特淋巴瘤)中，Pax5通常与已证实的癌基因Myc共同表达。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p53缺失的骨髓细胞被转导入 体内携带表达Myc的逆转录病毒。在同基因宿主中，这些细胞会导致侵袭性的、Pax5阳性的B细胞淋巴瘤。然而，从其衍生的一些细胞系自发地沉默Pax5并转变为髓系表型，并经常失去致瘤性。因此，Pax5的生理水平对Myc诱导的肿瘤的B淋巴样表型至关重要。此外，通过逆转录病毒转导获得的超生理学水平的Pax5被发现极大地促进了Myc诱导的肿瘤细胞的生长。在目前的提案中，将使用逆转录病毒转导系统来阐明Pax5在淋巴肿瘤发生中的确切作用。将解决三个重要问题。1.Pax5在限制Myc诱导的B淋巴瘤发生中的作用假设Myc转化的细胞是多能的。为了保持淋巴系血统并阻止髓系分化，他们需要Pax5作为前髓系转录的拮抗剂 因数PU.1。2.Pax5在骨髓细胞中的转化潜能。假说是，至少在没有P53的情况下，Pax5可以启动肿瘤生长，并取代Myc作为肿瘤的支撑。3.Pax5沉默对B淋巴母细胞瘤的影响。假说是，肿瘤前B细胞中Pax5的失活将导致致瘤性的丧失或减弱。这些实验结果可能确定Pax5是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.