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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-09
Application #
8533765
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$322,303
Indirect Cost
$50,311
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Cichocki, Frank; Verneris, Michael R; Cooley, Sarah et al. (2016) The Past, Present, and Future of NK Cells in Hematopoietic Cell Transplantation and Adoptive Transfer. Curr Top Microbiol Immunol 395:225-43
He, F; Warlick, E; Miller, J S et al. (2016) Lymphodepleting chemotherapy with donor lymphocyte infusion post-allogeneic HCT for hematological malignancies is associated with severe, but therapy-responsive aGvHD. Bone Marrow Transplant 51:1107-12
Weisdorf, Daniel (2016) The role of second transplants for leukemia. Best Pract Res Clin Haematol 29:359-364
Sarhan, Dhifaf; Cichocki, Frank; Zhang, Bin et al. (2016) Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. Cancer Res 76:5696-5706
Felices, Martin; Miller, Jeffrey S (2016) Targeting KIR Blockade in Multiple Myeloma: Trouble in Checkpoint Paradise? Clin Cancer Res 22:5161-5163
Schmohl, Joerg U; Felices, Martin; Taras, Elizabeth et al. (2016) Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modified IL-15 Cross-linker. Mol Ther 24:1312-22
Horowitz, Amir; Guethlein, Lisbeth A; Nemat-Gorgani, Neda et al. (2015) Regulation of Adaptive NK Cells and CD8 T Cells by HLA-C Correlates with Allogeneic Hematopoietic Cell Transplantation and with Cytomegalovirus Reactivation. J Immunol 195:4524-36
Holtan, Shernan G; Verneris, Michael R; Schultz, Kirk R et al. (2015) Circulating angiogenic factors associated with response and survival in patients with acute graft-versus-host disease: results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802. Biol Blood Marrow Transplant 21:1029-36
Holtan, Shernan G; DeFor, Todd E; Lazaryan, Aleksandr et al. (2015) Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 125:1333-8
Schlums, Heinrich; Cichocki, Frank; Tesi, Bianca et al. (2015) Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42:443-56

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