The overall goal of this proposal is to advance cure rates in the acute leukemias of childhood through clinically relevant study of key cellular and molecular aspects of these diseases. This broad objective will be pursued through five coordinated projects supported by administrative, biostatistical, and clinical trials Cores. Project 1 seeks to clarify the mechanism of action and assess the oncogenic potential of hepatic leukemic factor (HLF), a newly identified sequence-specific DNA-binding protein of the basic-region/leucine-zipper (bZip) superfamily. Parts of the gene encoding this factor become linked to elements of the E2A gene by the action of a t(17;19)(q22;p13) chromosomal translocation in childhood B-lineage acute lymphoblastic leukemia (ALL). This fusion gene results in chimeric proteins retaining the amino-terminal transcriptional activation domain of E2A, but not its basic helix-loop-helix domain, which is replaced by the HLF bZip DNA-binding and dimerization domain. In Project 2, human bone marrow progenitor cells will be marked with a retrovirally introduced gene (NeoR) to assess the contribution of reinfused marrow to relapse in patients with acute myelogenous leukemia (AML). If the marked cells are important in disease recurrent, a second hypothesis will be tested, namely, that marrow purging can remove the malignant blasts before infusion. Objectives of Project 3 are to determine the patient and/or disease characteristics influencing pharmacokinetics of certain antileukemic drugs in children to assess the relation of drug disposition to drug effects. these studies will contribute substantially to our goal of designing ALL chemotherapy that has maximal efficacy and minimal toxicity. The central goal of Project 4 is to determine whether a novel class of recently discovered """"""""G1 cyclins"""""""" contributes to the etiology of human leukemia. The rationale stems from the isolation of a family of growth factor-responsive cyclin D genes from CSF-1-stimulated macrophages and from recent data implicating these genes as relevant targets of both chromosomal translocations and gene amplification in human cancer. Project 5, will determine the mechanisms by which chromosomal rearrangements activate the EVI1 gene in leukemic blasts from cases of AML. The favored hypothesis is that EVI1 expression results from the introduction of sequences affecting chromatin structure over long distances. This planned 5-year program - integrating molecular, cellular and clinical studies - should contribute significantly to the accelerating progress in leukemia research worldwide.
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