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 Blood, 2 July 2009, Vol. 114, No. 1, pp. 202-210.
Prepublished online as a Blood First Edition Paper on May 5, 2009; DOI 10.1182/blood-2009-03-208801.

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TRANSPLANTATION

A chromosome 16 quantitative trait locus regulates allogeneic bone marrow engraftment in nonmyeloablated mice

Thai M. Cao1, Alun Thomas2, Yuanyuan Wang1, Schickwann Tsai1, Kathryn Logronio3, and Judith A. Shizuru3

1 Blood and Marrow Transplantation Program, Department of Medicine and 2 Department of Biomedical Informatics, University of Utah, Salt Lake City; and 3 Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, CA

Identifying genes that regulate bone marrow (BM) engraftment may reveal molecular targets for overcoming engraftment barriers. To achieve this aim, we applied a forward genetic approach in a mouse model of nonmyeloablative BM transplantation. We evaluated engraftment of allogeneic and syngeneic BM in BALB.K and B10.BR recipients. This allowed us to partition engraftment resistance into its intermediate phenotypes, which are firstly the immune-mediated resistance and secondly the nonimmune rejection of donor BM cells. We observed that BALB.K and B10.BR mice differed with regard to each of these resistance mechanisms, thereby providing evidence that both are under genetic control. We then generated a segregating backcross (n = 200) between the BALB.K and B10.BR strains to analyze for genetic linkage to the allogeneic BM engraftment phenotype using a 127-marker genome scan. This analysis identified a novel quantitative trait locus (QTL) on chromosome 16, termed Bmgr5 (logarithm of odds 6.4, at 11.1 cM). The QTL encodes susceptibility alleles, from the BALB.K strain, that are permissive for allogeneic BM engraftment. Further identification of Bmgr5 genes by positional cloning may reveal new and effective approaches for overcoming BM engraftment obstacles.


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