EXPLOITATION OF FREQUENT P16 DELETION IN T-ALL THERAPY

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DESCRIPTION: (Applicant's Abstract) This is a biological correlative study with two major objectives: (i) to delineate the clinical relevance of p16, a novel tumor suppressor gene and its related gene p15, in T-ALL; and (ii) to assess the frequent deletion of the gene which maps next to p16 and encodes for MTAP, with an aim to develop MTAP-targeted therapies for T-ALL. As a POG reference laboratory for tumor suppressor genes in T-ALL, the applicant plans to collect samples from T-ALL patients enrolled into the POG clinical trials, and carry out the following hypothesis-driven studies: Hypothesis 1: Alterations in p16/p15 genes are common in T-ALL at diagnosis and relapse, with deletion being more prevalent than mutations, and such alterations may be associated with poor clinical outcome. The approach will be to compare the frequency of p16/p15 alterations between diagnosis and relapse T-ALL samples and correlate the results with the clinical features of the patients, response to therapy and event free survival. Hypothesis 2: MTAP gene which is located adjacent to p16 gene, is often co-deleted in p16 deleted T-ALL samples. The approach will be to determine the frequency of deletion of the MTAP gene and compare the results with p16 gene status. Hypothesis 3: T-ALL cells which lack MTAP gene may display increased sensitivity to inhibitors of purine synthesis and increased dependence on methionine. This may lead to the development of new and selective therapies for T-ALL targeted at MTAP deficiency. The approach will be to determine the in vitro sensitivity of T-ALL cells to methionine depletion and purine synthesis inhibitors such as ddATHF (5,10- dideazatetrahydrofolate) and alanosine, and then correlate the results with MTAP gene status.