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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.
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Submitted February 26, 2007
Accepted April 2, 2007
Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen
Takakazu Kawase, Yoshiki Akatsuka*, Hiroki Torikai, Satoko Morishima, Akira Oka, Akane Tsujimura, Mikinori Miyazaki, Kunio Tsujimura, Koichi Miyamura, Seishi Ogawa, Hidetoshi Inoko, Yasuo Morishima, Yoshihisa Kodera, Kiyotaka Kuzushima, and Toshitada Takahashi
Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan
Dept of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan
Department of Genetic Information, Division of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan
Department of Internal Medicine & Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Department of Regeneration Medicine for Hematopoiesis, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan
* Corresponding author; email: yakatsuk{at}aichi-cc.jp.
Here we report the identification of a novel HLA-B44-restricted minor histocompatibility antigen (mHA) with expression limited to hematopoietic cells. cDNA expression cloning studies demonstrated that the 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 one 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)/ cnull mice was completely inhibited by in vitro preincubation with the mHA-specific cytotoxic T cell (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 post-transplant peripheral blood, while they were undetectable in pre-transplant 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 hematological malignancies.
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