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.
Showing the most recent 10 out of 14 publications
