Despite increasing cure rates, approximately one fourth of children with acute lymphoblastic leukemia (ALL) eventually die of their disease. The long-term objective of the proposed research is to improve the clinical outcomes of these patients. Early detection of residual disease after remission induction may identify patients who will benefit from intensified treatment, which should then boost the proportion of long-term survivors. During the previous funding period, sensitive immunologic methods of detecting minimal (i.e., submicroscopic) residual disease (MRD) in childhood ALL were developed, and a clinical study demonstrated that MRD detected by these methods is a powerful, independent prognostic indicator. The main remaining obstacle to the routine incorporation of MRD assays in treatment protocols for childhood ALL is the lack of practical methods that can be successfully applied to all patients. The objective of the studies proposed in Specific Aim 1 is to identify simple antibody panels that allow practical, reliable, and universal flow cytometric monitoring of MRD in children with ALL. Initial findings of cDNA array analyses will be integrated with information derived from comparing the gene profile of normal CD19+CD10+ cells to that of 284 newly diagnosed cases of B-lineage ALL. Flow cytometric studies will focus on proteins selected because of their overexpression in B-lineage ALL cells and their predicted localization on the cell surface. Studies proposed in Specific Aim 2 seek to determine whether detectable MRD in peripheral blood is associated with a more aggressive form of B-lineage ALL as suggested by preliminary results. Studies under this aim will also assess whether the propensity of B-lineage ALL cells to prematurely exit the bone marrow microenvironment is associated with characteristic patterns of expression of adhesion molecules, chemokine receptors or matrix-degrading metalloproteinases. Studies in Specific Aim 3 will determine whether peripheral-blood MRD levels reflect those in the bone marrow in children with T-lineage ALL in clinical remission, as suggested by preliminary results. Success in this endeavor could radically improve remission studies in these patients by overcoming the practical and ethical constraints posed by sequential bone marrow aspirations
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