TEL/AML1 FUSION IN PEDIATRIC ALL

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DESCRIPTION: (adapted verbatim from the investigator's abstract) TEL/AML1 is the most common gene rearrangement in pediatric acute lymphoblastic leukemia (ALL), accounting for approximately 25% of cases. The PI and others, have reported that TEL/AML1 confers a favorable prognosis in retrospective studies. However, controversy has arisen regarding the prognostic value of TEL-AML1. Two centers have recently reported that the incidence of TEL/AML1 at relapse is similar to that at diagnosis, suggesting that the rearrangement does not confer a favorable prognosis. The disparity may reflect true differences in outcome between centers for this subgroup of patients, or may reflect the selection bias inherent in retrospective studies. The first specific aim of this proposal will test the hypothesis that TEL/AML1 confers a favorable prognosis in a prospective trail. The incidence and prognostic significance of the TEL/AML1 gene rearrangement will be determined prospectively in children with newly diagnosed ALL. They will further determine whether quantitative minimal residual disease measurements can delineate those TEL/AML1 positive patients that are cured of their disease versus those that are destined to relapse. The second specific aim is to develop a murine model for TEL/AML1 leukemia. Preliminary data indicates that expression of TEL/AML1 alone is not sufficient for transformation of hematopoietic cells in vitro or in vivo. They will test the hypothesis that additional mutations that are present in human leukemic cells with the TEL/AML1 rearrangement are required for transformation mediated by TEL/AML1. It is known that the TEL/AML1 gene rearrangement is associated with loss of the residual TEL allele, and that a subset of TEL/AML1 positive patients are p16 deficient. They will therefore focus on strategies that will allow for expression of TEL/AML1 in both TEL and p16 deficient backgrounds. The two specific aims of this proposal are complementary. The first specific aim should provide definitive information about the prognostic value of the TEL/AML1 gene rearrangement in pediatric B cell ALL. Based on these data, it may be possible to consider alternative approaches to therapy of ALL. Specific aim 2 will focus on the development of an animal model of TEL/AML1-mediated leukemia that may prove useful in testing and evaluating alternative approaches, and defining those genetic events that are critical for the transformation of hematopoietic cells.