) TEL/AML1 is the most common gene rearrangement in pediatric acute lymphoblastic leukemia (ALL), accounting for approximately 25 percent of cases. We 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 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.
Specific Aim 1 of this proposal will test the hypothesis that TEL/AML1 confers a favorable prognosis. The incidence and prognostic significance of the TEL/AML1 gene rearrangement will be prospectively determined in children with newly diagnosed ALL treated on DFCI protocols 95-01 and 2000-01. We will further determine whether quantitative minimal residual disease measurements can delineate TEL/AML1 positive patients that are cured of their disease versus those that are destined to relapse.
Specific Aim 2 is to develop a murine model for TEL/AML1 leukemia. Our preliminary data indicate that expression of TEL/AML1 alone is not sufficient for transformation of hematopoietic cells in vitro or in vivo. We will test the hypothesis that additional mutations, present in human leukemic cells with the TEL/AML1 rearrangement, are required for transformation mediated by TEL/AML1. These include loss of the residual TEL allele, and hemizygous loss of the neighboring tumor suppressor gene p27/KIP1. In addition, a subset of TEL/AML1 positive patients are p16 deficient. We have developed strategies for expression of TEL/AML1 in each of these genetic backgrounds, including the construction of a conditional Tel allele in mice. The two Specific Aims of this proposal are complementary. The first Specific Aim will provide definitive information on prognosis of the TEL/AML1 gene rearrangement in pediatric B-cell ALL, and may provide a rationale for considering alternative approaches to therapy.
Specific Aim 2 will focus on the development of an animal model of TEL/AML1-mediated leukemia, which would be valuable for testing alternative approaches to therapy, and in defining the genetic events that are critical for the transformation of hematopoietic cells.
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