The HLA/lmmunogenetics Laboratory, directed by Dr. Elizabeth trachtenberg at Children's Hospital Oakland Research Institute (CHORI), will continue in their role as the KIR Genotyping Core Laboratory to explore in further detail the hetrogeneity of KIR at the allelic level, and the role of KIR-HLA associations in unrelated hematopoietic stem cell transplantations (HCT) for acute myelogenous leukemia (AML). Data from this core was key to the Project's seminal analyses of KIR and HLA ligand genetics in HCT showing improved relapse-free survival with B haplotype donors in HCT for AML(detailed in Projects 1 and 3). The Laboratory has a proven track record with high-throughput, high complexity genetic analyses and assay development, and have the necessary quality assurance expertise and equipment necessary to fulfill this role. The KIR Genotyping Core Laboratory will analyze samples requiring locus-specific characterization using the well proven MALDI-TOF assay, or clinically validated sequence-specific priming (SSP) kits. The Laboratory will next shift into KIR allelic analysis utilizing a novel, next-generation clonal sequencing of all KIR genes. Formal validation of our novel protocol to characterize all ofthe KIR loci on multiple samples simultaneously, utilizing the Roche 454 Genome Sequencer FLX Titanium platform, will be finished in the first year of this POI renewal, and a computer program to analyze the data and report all KIR alleles will be developed in collaboration with Dr. Damian Goodridge (Conexio Genomics).
The specific aims of this Core Laboratory for the five year time period are: 1) continue refinement and validation of our KIR sequencing assay to clonally sequence all KIR genes on samples using the Roche GS FLX platform;2a) perform KIR allelic sequencing of samples in support of a retrospective study of outcome analysis of HCT for AML (Project 1), and 2b) to perform locus-specific KIR analysis of samples for studies within the critical time frames required forthe prospective clinical studies (Projects 2 and 3);and 3) implement a quality assurance (QA) program, including 15% duplicate and blinded typings. No other lab is as prepared to provide the rapid KIR genotyping and QA measures necessary to adequately serve the typing needs of these projects.
KIR genotyping results in superior relapse free survival using B/x donors in HCT for AML. This association with be refined to tease out genetic components that best predict clinical benefit. Development of nextgeneration sequencing methods to analyze KIR alleles will change practice by providing a comprehensive overview on the role of both inhibitory and stimulatory KIR alleles acting alone or in combination in HCT.
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