PAX5基因突变在儿童急性白血病中的致病机理

Pax5 is a B cell specific transcription factor essential for B lineage cell development. Recent studies uncovered that Pax5 gene is mutated in 32% acute lymphoblastic leukemia (ALL), indicating that mutant Pax5 contributes to leukemogenesis. However, how mutation of Pax5 gene casues ALL is still not clear. To understanding the underlying mechanism, we analyzed the role of Pax5 in regulating cell proliferation. We found that over expression of the wild type Pax5 in different mouse or human B cell lines inhibits cell proliferation. In Pax5-/- murine pro-B cells, forced expression of Pax5 inhibits Cyclin D1 and D2 expression. Mutation to Pax5 diminished such inhibition on Cyclin D1, D2 expression, and cell proliferation. Long term expression of mutant Pax5 even created a growth advantage in vitro. We hypothesize that normally Pax5 acts as a negative regulator for B cell proliferation through inhibition of Cyclin D1 and D2 expression. Mutation of Pax5 may disrupt this negative regulation and contribute to leukemogenesis. We will analyze Pax5 mutation in Chinese childhood ALL patients. We will determine if overexpression of mutant Pax5 in cell or mouse model will disrupt Pax5-mediated inhibition of cell proliferation and thus cause leukemia in mice. We will further explore how Pax5 mutation cause ALL in addition to inhibition of Cyclin D1/D2 expression.

Pax5是B细胞发育必须的转录因子。Pax5 基因在32%儿童急性淋巴细胞白血病(ALL)中发生突变，表明Pax5突变可能导致白血病。Pax5基因突变如何导致白血病的分子机制还没有被阐明。为了揭示Pax5突变如何导致ALL，我们发现在人或者小鼠B细胞中过度表达Pax5抑制细胞增殖。在Pax5-/-小鼠祖B细胞中，高表达Pax5抑制细胞因子Cyclin D1和D2表达；突变的Pax5失去了对Cyclin D1、D2以及细胞增殖的抑制。长期表达突变的Pax5反而促进细胞生长。我们假设Pax5通常作为一个B细胞增殖的负调控因子抑制Cyclin D1和D2的表达。Pax5突变可能改变了这个负调控机制，进而导致白血病。我们将利用高通量测序来分析中国儿童ALL中Pax5基因突变的分布。我们将利用细胞和小鼠模型研究从ALL患者所发现的Pax5突变是否失去对细胞增殖的抑制，从而在小鼠里引起白血病。我们还将进一步探讨Pax5除了抑制CyclinD1/D2外导致ALL的其他可能的机制。

Pax5是B细胞发育必须的转录因子。我们发现在人或者小鼠B细胞中过度表达Pax5抑制细胞因子Cyclin D1和D2表达，抑制细胞增殖。我们还发现Pax5和细胞核骨架结合，Pax5 K67，K87，K89 和P80突变不能和细胞核骨架结合，从而失去了对下游目标基因的调控作用，也失去了对Cyclin D1、D2以及细胞增殖的抑制。长期表达这些Pax5突变体，不再抑制细胞增殖，反而促进细胞生长。这些发现第一次表明Pax5是一个细胞增殖的负调控因子。更重要的是Pax5的生物活性需要通过和细胞核骨架结合来完成。