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, Toshitada Takahashi

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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)/γcnull 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.

Original languageEnglish
Pages (from-to)1055-1063
Number of pages9
JournalBlood
Volume110
Issue number3
DOIs
Publication statusPublished - 01-08-2007
Externally publishedYes

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Minor Histocompatibility Antigens
Alternative Splicing
Single Nucleotide Polymorphism
T-cells
Cytotoxic T-Lymphocytes
Blood
Stem cells
Clone Cells
Myeloid Progenitor Cells
T-Lymphocytes
RNA Splice Sites
Myeloid Leukemia
T-Lymphocyte Epitopes
SCID Mice
Cloning
Hematologic Neoplasms
HLA Antigens
Blood Donors
Polymorphism
Immunotherapy

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Kawase, T., Akatsuka, Y., Torikai, H., Morishima, S., Oka, A., Tsujimura, A., ... Takahashi, T. (2007). Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. Blood, 110(3), 1055-1063. https://doi.org/10.1182/blood-2007-02-075911
Kawase, Takakazu ; Akatsuka, Yoshiki ; Torikai, Hiroki ; Morishima, Satoko ; Oka, Akira ; Tsujimura, Akane ; Miyazaki, Mikinori ; Tsujimura, Kunio ; Miyamura, Koichi ; Ogawa, Seishi ; Inoko, Hidetoshi ; Morishima, Yasuo ; Kodera, Yoshihisa ; Kuzushima, Kiyotaka ; Takahashi, Toshitada. / Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. In: Blood. 2007 ; Vol. 110, No. 3. pp. 1055-1063.
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abstract = "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)/γcnull 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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Kawase, T, Akatsuka, Y, Torikai, H, Morishima, S, Oka, A, Tsujimura, A, Miyazaki, M, Tsujimura, K, Miyamura, K, Ogawa, S, Inoko, H, Morishima, Y, Kodera, Y, Kuzushima, K & Takahashi, T 2007, 'Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen', Blood, vol. 110, no. 3, pp. 1055-1063. https://doi.org/10.1182/blood-2007-02-075911

Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. / Kawase, Takakazu; Akatsuka, Yoshiki; Torikai, Hiroki; Morishima, Satoko; Oka, Akira; Tsujimura, Akane; Miyazaki, Mikinori; Tsujimura, Kunio; Miyamura, Koichi; Ogawa, Seishi; Inoko, Hidetoshi; Morishima, Yasuo; Kodera, Yoshihisa; Kuzushima, Kiyotaka; Takahashi, Toshitada.

In: Blood, Vol. 110, No. 3, 01.08.2007, p. 1055-1063.

Research output: Contribution to journalArticle

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T1 - Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen

AU - Kawase, Takakazu

AU - Akatsuka, Yoshiki

AU - Torikai, Hiroki

AU - Morishima, Satoko

AU - Oka, Akira

AU - Tsujimura, Akane

AU - Miyazaki, Mikinori

AU - Tsujimura, Kunio

AU - Miyamura, Koichi

AU - Ogawa, Seishi

AU - Inoko, Hidetoshi

AU - Morishima, Yasuo

AU - Kodera, Yoshihisa

AU - Kuzushima, Kiyotaka

AU - Takahashi, Toshitada

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N2 - 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)/γcnull 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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Kawase T, Akatsuka Y, Torikai H, Morishima S, Oka A, Tsujimura A et al. Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. Blood. 2007 Aug 1;110(3):1055-1063. https://doi.org/10.1182/blood-2007-02-075911