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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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TRANSPLANTATION
Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen
Takakazu Kawase1,2,
Yoshiki Akatsuka1,
Hiroki Torikai1,
Satoko Morishima1,2,
Akira Oka3,
Akane Tsujimura4,
Mikinori Miyazaki5,
Kunio Tsujimura1,
Koichi Miyamura3,
Seishi Ogawa6,7,
Hidetoshi Inoko4,
Yasuo Morishima8,
Yoshihisa Kodera4,
Kiyotaka Kuzushima1, and
Toshitada Takahashi1,2
1 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)/ 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.
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