MOLECULAR MECHANISM OF HEMATOLOGICAL MALIGNANCY

急性淋巴细胞白血病（T-ALL）的诱导机制是 不知道。 我们也不知道为什么T-ALL患者复发时如此高， 频率. 如果诱导和复发的分子机制 T-ALL都被理解了，也许有可能设计出合理的 逆转或治愈这种疾病的策略。 的不同机制 已经提出了T-ALL的诱导。 一个合理的建议 靶向分化失调作为起始事件。 前T细胞或前T细胞的分化失调会导致 非程序性细胞自我更新和细胞凋亡 衰老 在本申请中，我们表明， 分化可能与以下基因的缺失或突变有关： 特异性肿瘤抑制基因（TS）。 两个国家地位的研究 T-ALL细胞系中已知的TS基因揭示了60%的T-ALL 株系具有突变的p53 TS基因，20%的株系丧失了p53 TS基因。 视网膜母细胞瘤易感基因产物Rb。 此外，新鲜T- 还发现所有样本都具有p53突变， 基因 T-ALL中这些TS基因丢失的高发生率 细胞，以及p53/Rb与细胞作用的关系 分化/增殖强烈表明， p53/RB基因分别在细胞凋亡中起重要作用。 T-ALL的诱导和/或复发。 因此，我们建议 研究T-ALL的诱导机制（i）通过研究 初步诊断和复发T-ALL患者样品中的p53;（ii） 通过研究p53在原发性肝癌和复发性肝癌中的地位， 相同患者的样本，以确定p53 突变和T-ALL细胞“进展”;（iii）通过研究 p53对白血病T母细胞分化的影响;以及（iv）通过 设计逆转T-ALL细胞白血病状态的策略 通过导入野生型p53和/或Rb基因构建体。 由于T细胞中所有的恶性抑制基因 白血病发生似乎是迄今为止最有希望的方法， 实现白血病状态的生物学逆转。

The mechanism of induction of acute lymphoblastic leukemia (T-ALL) is not known. Nor do we know why T-ALL patients relapse with such high frequency. If the molecular mechanism of induction and of relapse of T-ALL were understood, it might be possible to design rational strategies to reverse or cure this disease. Different mechanisms for the induction of T-ALL have been proposed. One reasonable suggestion targets dysregulation of differentiation as an initiating event. Disregulation of differentiation of pro- or pre- T cells would cause unscheduled cellular self-renewal and the abrogation of cell senescence. In this application we show that dysregulation of differentiation may be associated with the loss or mutation of specific tumor suppressor (TS) genes. A study of the status of two known TS genes in T-ALL cell lines has revealed that 60% of T-ALL lines possessed mutated p53 TS genes, and 20% had lost the retinoblastoma susceptibility gene product Rb. Furthermore, fresh T- ALL samples have also been found to possess mutations of the p53 gene. The high incidence of loss of these TS genes among T-ALL cells, and the relationship between the roles of p53/Rb and cell differentiation/proliferation strongly suggest that mutation/loss of the p53/RB genes, respectively, plays a significant role in the induction and/or the recurrence of T-ALL. Therefore we propose to study the mechanism of induction of T-ALL (i) by studying the status of p53 in primary diagnosis and relapse T-ALL patient samples; (ii) By studying the status of p53 in primary diagnosis and relapse samples of the same patients to determine the relationship of p53 mutation and T-ALL cell "progression"; (iii) By studying the effects of p53 on the differentiation of leukemic T blasts; and (iv) by designing strategies for reversing the leukemic state of T-ALL cells through the introduction of wild type p53 and/or Rb gene constructs. Since all malignancy-conferring suppressor genes in T-cell leukemogenesis appears to be the most promising approach to date for achieving the biological reversion of the leukemic state.