MOLECULAR MECHANISM OF HEMATOLOGICAL MALIGNANCY

急性淋巴细胞白血病(T-ALL)的诱发机制是 不知道。我们也不知道为什么T-ALL患者的复发率这么高 频率如果诱发和复发的分子机制 所有这些都是理解的，所以有可能设计出Rational 逆转或治愈这种疾病的策略。不同的机制 T-ALL的诱导已被提出。一个合理的建议 将分化失调作为启动事件。 T细胞前或前T细胞分化的失调将导致 细胞的非程序性自我更新与细胞的消灭 衰老。在本应用程序中，我们展示了 分化可能与基因缺失或突变有关。 特异性肿瘤抑制因子(TS)基因。关于两个国家地位的研究 T-ALL细胞系中已知的TS基因显示60%的T-ALL 具有突变的p53 TS基因的品系中，有20%的品系丢失了 视网膜母细胞瘤易感基因产物Rb。此外，新鲜的T- 所有样本也都被发现存在p53突变。 吉恩。T-ALL中TS基因缺失的高发率 细胞以及P53/Rb的作用与细胞的关系 分化/增殖强烈提示基因突变/缺失 P53/Rb基因分别在卵巢癌中起着重要作用。 T-ALL的诱导和/或复发。因此，我们建议 通过研究T-ALL的状态来研究T-ALL的诱导机制 P53在初诊和复发T-ALL患者样本中的表达；(Ii) 通过研究P53在初诊和复发中的地位 同一患者标本中P53蛋白的相关性研究 突变与T-ALL细胞“进展”；(Iii)通过研究 P53对白血病T细胞分化的影响；及 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。 由于T细胞中所有与肿瘤相关的抑制基因 白血病的发生似乎是迄今为止最有希望的治疗方法。 实现白血病状态的生物逆转。

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.