BACKTRACKING TRANSLOCATIONS IN CHILDHOOD LEUKEMIA

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DESCRIPTION (Adapted from investigator's abstract): The etiology of childhood leukemia is currently being examined under large-scale epidemiology studies in the US and UK. The investigator proposes to examine the timing and etiology of the most frequent genetic aberrations in childhood acute lymphoblastic and myeloblastic leukemia (ALL and AML) by using molecular biology and bioinformatic tools and resources in patient diagnostic and archived materials. The investigator has previously shown that the most common translocation in childhood leukemia, t(12;21) (or TEL-AML1 gene fusion) can occur before birth in a small number of individuals who later developed childhood leukemia. These studies will be expanded and extended to an independent population in California. About 150 patients with specific aberrations, including t(12;21), t(1;19), t(8;21), and NRAS mutations, will be "backtracked" by screening for the aberration in the neonatal heel-prick Guthrie spots that were taken at birth. The aberrations will first be characterized at the genomic DNA level, and then will be used as clonotypic markers in sensitive screening assays of Guthrie spots. In addition to this use as markers of leukemia cell clones, translocation fusion sequences provide insight into the processes that formed the fusion. TEL-AML1 fusion junctions tend to group into "micro-clusters," or distinct regions within the larger intronic breakpoint cluster regions. The micro-clustering is independent of the structure of the chimeric oncogenic protein, which is the same for all patients. Micro-clustering of breakpoints in certain areas suggests that features of the intrinsic DNA sequence or chromatin structure are critical in the process of formation of the translocation. These features will be probed by statistically based DNA sequence recognition tools along with a coordinated laboratory analysis to identify sequence motifs. A final goal of the project is to develop methods to sensitively track leukemia clones in treated patients in order to gauge the success of therapy. In summary, this project aims to elucidate the timing and structure of the genetic events that lead to childhood leukemia.