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Blood, 1 August 2007, Vol. 110, No. 3, pp. 1055-1063. Prepublished online as a Blood First Edition Paper on April 4, 2007; DOI 10.1182/blood-2007-02-075911.
TRANSPLANTATION Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen1 Division of Immunology, Aichi Cancer Center Research Institute, Aichi; 2 Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya; 3 Department of Genetic Information, Division of Molecular Life Science, Tokai University School of Medicine, Isehara; 4 Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya; 5 Department of Internal Medicine & Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya; 6 Core Research for Evolutional Science and Technology (CREST) of Japan, Science and Technology Corporation (JST), Saitama; 7 Department of Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, Tokyo; 8 Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan
Here we report the identification of a novel human leukocyte antigen (HLA)-B44–restricted minor histocompatibility antigen (mHA) with expression limited to hematopoietic cells. cDNA expression cloning studies demonstrated that the cytotoxic T lymphocyte (CTL) epitope of interest was encoded by a novel allelic splice variant of HMSD, hereafter designated as HMSD-v. The immunogenicity of the epitope was generated by differential protein expression due to alternative splicing, which was completely controlled by 1 intronic single-nucleotide polymorphism located in the consensus 5' splice site adjacent to an exon. Both HMSD-v and HMSD transcripts were selectively expressed at higher levels in mature dendritic cells and primary leukemia cells, especially those of myeloid lineage. Engraftment of mHA+ myeloid leukemia stem cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID)/
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
cnull mice was completely inhibited by in vitro preincubation with the mHA-specific CTL clone, suggesting that this mHA is expressed on leukemic stem cells. The patient from whom the CTL clone was isolated demonstrated a significant increase of the mHA-specific T cells in posttransplantation peripheral blood, whereas mHA-specific T cells were undetectable in pretransplantation peripheral blood and in peripheral blood from his donor. These findings suggest that the HMSD–v–encoded mHA (designated ACC-6) could serve as a target antigen for immunotherapy against hematologic malignancies. 
