The relevance of human leukocyte antigen in the development and progression of latently infected virus-associated lymphoid malignancies.

• Project/Area Number: 17K09934
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of the Ryukyus
• Principal Investigator: Morishima Satoko 琉球大学, 医学(系)研究科(研究院), 准教授 (40463195)
• Co-Investigator(Kenkyū-buntansha): 益崎 裕章 琉球大学, 医学(系)研究科(研究院), 教授 (00291899) ; 玉城 啓太 琉球大学, 医学(系)研究科(研究院), 客員研究員 (40806452)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HLA / 潜伏感染ウイルス / リンパ系腫瘍 / 成人T細胞白血病リンパ腫 / HTLV-I / 成人T細胞白血病・リンパ腫 / 血液腫瘍学 / 免疫学

Outline of Final Research Achievements

Human leukocyte antigen (HLA) plays a critical role in the immune response, and reduced expression of HLA is associated with poor prognosis in various types of cancers. We explored the relevance of HLA in the pathogenesis and progression of adult T-cell leukemia lymphoma (ATL). Using a next-generation sequencing (NGS)-based high-resolution HLA DNA typing method, which successfully covers the entire region of HLA genes, we analyzed eight classical HLA loci in 25 pairs of ATL and non-ATL cells from the same patients. Multiple HLA gene alterations were concurrently observed in ATL cells within the same patients, possibly reducing cell-surface expression of HLA class I molecules. In contrast, no HLA alterations were detected in five patients with chronic-type ATL. HLA alterations were associated with aggressive phenotypes, raising a possibility that ATL cells can develop immune escape mechanisms through a variety of acquired alterations in HLA genes.

Academic Significance and Societal Importance of the Research Achievements

Long-range法を用いることでATL細胞に生じるHLA遺伝子異常の特徴を明らかにすることができた。従来のHLAタイピング法では検出されないイントロンや多型に富むエクソン以外にも遺伝子異常を認め、がん細胞に生じるHLA遺伝子異常を正確に検出するためにはlong-range法を用いることが重要であることを示した。
ATLの急性型ではHLAの遺伝子異常を獲得しやすい可能性があり、ATLに対して同種移植やワクチン療法などを実施する際に、本解析によって得られる結果は治療効果を予測する上で重要な情報となる可能性がある。

Research Products

• [Journal Article] Sequence Variations Within HLA-G and HLA-F Genomic Segments at the Human Leukocyte Antigen Telomeric End Associated With Acute Graft-Versus-Host Disease in Unrelated Bone Marrow Transplantation. (2022)
  • Author(s): Suzuki S, Morishima S, Murata M, Tanaka M, Shigenari A, Ito S, Kanga U, Kulski JK, Morishima Y, Shiina T.
  • Journal Title: Front Immunol. Volume: 13 Pages: 938206-938206
  • DOI: 10.3389/fimmu.2022.938206
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Race and Survival in Unrelated Hematopoietic Cell Transplantation. (2022)
  • Author(s): Morishima Y, Morishima S, Stevenson P, Kodera Y, Horowitz M, McKallor C, Malkki M, Spellman SR, Gooley T, Petersdorf EW.
  • Journal Title: Transplant Cell Ther. Volume: 28 Issue: 7 Pages: 357-357
  • DOI: 10.1016/j.jtct.2022.03.026
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of HLA Epitope Matching on Outcomes After Unrelated Bone Marrow Transplantation (2022)
  • Author(s): Iwasaki Makoto、Kanda Junya、Tanaka Hidenori、Shindo Takero、Sato Takahiko、Doki Noriko、Fukuda Takahiro、Ozawa Yukiyasu、Eto Tetsuya、Uchida Naoyuki、Katayama Yuta、Kataoka Keisuke、Ara Takahide、Ota Shuichi、Onizuka Makoto、Kanda Yoshinobu、Ichinohe Tatsuo、Atsuta Yoshiko、Morishima Satoko
  • Journal Title: Frontiers in Immunology Volume: 13 Pages: 811733-811733
  • DOI: 10.3389/fimmu.2022.811733
  • Peer Reviewed / Open Access
• [Journal Article] Improved outcomes of single-unit cord blood transplantation for acute myeloid leukemia by killer immunoglobulin-like receptor 2DL1-ligand mismatch. (2022)
  • Author(s): Yokoyama H, Kanaya M, Iemura T, Hirayama M, Yamasaki S, Kondo T, Uchida N, Takahashi S, Tanaka M, Onizuka M, Ozawa Y, Kozai Y, Eto T, Sugio Y, Hamamura A, Kawakita T, Aotsuka N, Takada S, Wake A, Kimura T, Ichinohe T, Atsuta Y, Yanada M, Morishima S.
  • Journal Title: Bone Marrow Transplant. Volume: 57 Issue: 7 Pages: 1171-1179
  • DOI: 10.1038/s41409-022-01700-y
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Multiple HLA Locus Mismatches on Outcomes after Single Cord Blood Transplantation. (2022)
  • Author(s): Kanda J, Hirabayashi S, Yokoyama H, Kawase T, Tanaka H, Uchida N, Taniguchi S, Takahashi S, Onizuka M, Tanaka M, Sugio Y, Eto T, Kanda Y, Kimura T, Ichinohe T, Atsuta Y, Morishima S.
  • Journal Title: Transplant Cell Ther. Volume: 28 Issue: 7 Pages: 398-398
  • DOI: 10.1016/j.jtct.2022.05.005
  • Peer Reviewed / Open Access
• [Journal Article] Impact of human leukocyte antigen mismatch on outcomes after unrelated bone marrow transplantation in paediatric patients: A retrospective analysis by the JSTCT HLA working group. (2022)
  • Author(s): Kato I, Sakaguchi H, Kato S, Sato M, Noguchi M, Yoshida N, Koh K, Koike T, Yanagimachi M, Kato K, Takahashi Y, Fujita N, Sato A, Hashii Y, Tabuchi K, Atsuta Y, Morishima S, Kanda J.
  • Journal Title: Br J Haematol. Volume: 199 Issue: 3 Pages: 392-400
  • DOI: 10.1111/bjh.18425
  • Peer Reviewed / Open Access
• [Journal Article] Full-length HLA sequencing in adult T cell leukemia-lymphoma uncovers multiple gene alterations. (2021)
  • Author(s): Tamaki K, Morishima S, Suzuki S, Shigenari A, Nomura I, Yokota Y, Morichika K, Nishi Y, Nakachi S, Okamoto S, Fukushima T, Shiina T, Masuzaki H.
  • Journal Title: Leukemia Volume: 35 Issue: 10 Pages: 2998-3001
  • DOI: 10.1038/s41375-021-01403-1
  • Peer Reviewed / Open Access
• [Journal Article] Individual HLAs influence immunological events in allogeneic stem cell transplantation from HLA-identical sibling donors. Bone Marrow Transplant. (2021)
  • Author(s): Morishima S, Fukuda T, Doki N, Mori T, Onizuka M, Kawakita T, Kato C, Ozawa Y, Tanaka M, Kurokawa M, Kamimura T, Inoue M, Tanaka J, Ichinohe T, Atsuta Y, Morishima Y.
  • Journal Title: Bone Marrow Transplant. Volume: 56 Issue: 3 Pages: 646-654
  • DOI: 10.1038/s41409-020-01070-3
  • Peer Reviewed / Open Access
• [Journal Article] Capturing Differential Allele-Level Expression and Genotypes of All Classical HLA Loci and Haplotypes by a New Capture RNA-Seq Method. (2020)
  • Author(s): Yamamoto F, Suzuki S, Mizutani A, Shigenari A, Ito S, Kametani Y, Kato S, Fernandez-Vina M, Murata M, Morishima S, Morishima Y, Tanaka M, Kulski JK, Bahram S, Shiina T.
  • Journal Title: Front Immunol. Volume: 11 Pages: 941-941
  • DOI: 10.3389/fimmu.2020.00941
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 造血細胞移植を成功に導くHLA研究 (2020)
  • Author(s): 森島聡子
  • Journal Title: 臨床免疫・アレルギー科 Volume: 74 Pages: 456-461
• [Journal Article] Transplant-related complications are impediments to the success of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia patients in non-complete remission. (2020)
  • Author(s): Tomori S, Morishima S, Nishi Y, Nakachi S, Tamaki K, Morichika K, Tedokon I, Shimabukuro N, Hanashiro T, Kitamura S, Uchibori S, Miyagi R, Miyagi T, Karimata K, Ohama M, Yamanoha A, Tomoyose T, Karube K, Fukushima T, Masuzaki H.
  • Journal Title: Bone Marrow Transplant. Volume: 55 Issue: 1 Pages: 233-241
  • DOI: 10.1038/s41409-019-0669-z
  • Peer Reviewed / Open Access
• [Journal Article] Implications of HLA in allogeneic stem cell transplantation (2019)
  • Author(s): Morishima S
  • Journal Title: Rinsho Ketsueki Volume: 60 Issue: 9 Pages: 1324-1330
  • DOI: 10.11406/rinketsu.60.1324
  • NAID: 130007724650
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] A pilot assessment of xanthine oxidase activity in plasma from patients with hematological malignancies using a highly sensitive assay. (2019)
  • Author(s): Hokama N, Shirakura T, Sunagawa S, Morishima S, Nakachi S, Nishi Y, Murayama Y, Matsui C, Hase N, Tamura M, Okamoto S, Shimabukuro M, Nakamura K, Masuzaki H.
  • Journal Title: Hematol Oncol. Volume: 37 Issue: 4 Pages: 527-530
  • DOI: 10.1002/hon.2659
  • Peer Reviewed / Open Access
• [Journal Article] Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma. (2019)
  • Author(s): Morichika K, Karube K, Kayo H, Uchino S, Nishi Y, Nakachi S, Okamoto S, Morishima S, Ohshiro K, Nakazato I, Fukushima T, Masuzaki H.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 9 Pages: 2982-2991
  • DOI: 10.1111/cas.14114
  • NAID: 120006937802
  • Peer Reviewed / Open Access
• [Journal Article] Defective Epstein-Barr virus in chronic active infection and haematological malignancy. (2019)
  • Author(s): Okuno Y, Murata T, Sato Y,Yoshida K, Sawada A, Inoue M, Kawa K, Seto M, Ohshima K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Nishida T, Kiyoi H, Kato S, Nakamura S, Morishima S, Yoshikawa T, Fujiwara S, Shimizu N, Isobe Y, Noguchi M, Kikuta A, Iwatsuki K, Takahashi Y, Kojima S, Ogawa S, Kimura H.
  • Journal Title: Nat Microbiol. Volume: 4 Issue: 3 Pages: 404-413
  • DOI: 10.1038/s41564-018-0334-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reference Grade Characterization of Polymorphisms in Full-Length HLA Class I and II Genes With Short-Read Sequencing on the ION PGM System and Long-Reads Generated by Single Molecule, Real-Time Sequencing on the PacBio Platform. (2018)
  • Author(s): Suzuki S, Ranade S, Osaki K, Ito S, Shigenari A, Ohnuki Y, Oka A, Masuya A, Harting J, Baybayan P, Kitazume M, Sunaga J, Morishima S, Morishima Y, Inoko H, Kulski JK, Shiina T.
  • Journal Title: Front Immunol. Volume: 9 Pages: 2294-2294
  • DOI: 10.3389/fimmu.2018.02294
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of two prognostic indices for adult T-cell leukemia/lymphoma in the subtropical endemic area, Okinawa, Japan. (2018)
  • Author(s): Tamaki K, Morishima S, Nomura S, Nishi Y, Nakachi S, Kitamura S, Uchibori S, Tomori S, Hanashiro T, Shimabukuro N, Tedokon I, Morichika K, Taira N, Tomoyose T, Miyagi T, Karimata K, Ohama M, Yamanoha A, Tamaki K, Hayashi M, Uchihara JN, Ohshiro K, Asakura Y, Kuba-Miyara M, Karube K, Fukushima T, Masuzaki H.
  • Journal Title: Cancer Sci. Volume: 109 Issue: 7 Pages: 2286-2293
  • DOI: 10.1111/cas.13641
  • NAID: 120006937800
  • Peer Reviewed / Open Access
• [Journal Article] Evolutionary basis of HLA-DPB1 alleles affects acute GVHD in unrelated donor stem cell transplantation. (2018)
  • Author(s): Morishima S, Shiina T, Suzuki S, Ogawa S, Sato-Otsubo A, Kashiwase K, Azuma F, Yabe T, Satake M, Kato S, Kodera Y, Sasazuki T, Morishima Y
  • Journal Title: Blood Volume: 131(7) Issue: 7 Pages: 808-817
  • DOI: 10.1182/blood-2017-08-801449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Risk of HLA Homozygous Cord Blood Transplantation: Implications for Induced Pluripotent Stem Cell Banking and Transplantation. (2018)
  • Author(s): Morishima Y, Azuma F, Kashiwase K, Matsumoto K, Orihara T, Yabe H, Kato S, Kato K, Kai S, Mori T, Nakajima K, Morishima S, Satake M, Takanashi M, Yabe T
  • Journal Title: Stem Cells Transl Med. Volume: 7(2) Issue: 2 Pages: 173-179
  • DOI: 10.1002/sctm.17-0169
  • Peer Reviewed / Open Access
• [Journal Article] HLA-DPB1 mismatch induces a graft-versus-leukemia (GVL) effect without severe acute GVHD after single-unit umbilical cord blood transplantation (2018)
  • Author(s): Yabe T, Azuma F, Kashiwase K, Matsumoto K, Orihara T, Yabe H, Kato S, Kato K, Kai S, Mori T, Morishima S, Satake M, Takanashi M, Nakajima K, Morishima Y
  • Journal Title: Leukemia Volume: 168-175 Issue: 1 Pages: 168-175
  • DOI: 10.1038/leu.2017.202
  • Peer Reviewed
• [Journal Article] Clinical usefulness of FDG?PET/CT for the evaluation of various types of adult T-cell leukemia (2017)
  • Author(s): Nakachi Sawako、Okada Masahiro、Morishima Satoko、Agarie Yurika、Kitamura Sakiko、Uchibori Sachie、Tomori Shouhei、Hanashiro Taeko、Shimabukuro Natsuki、Tamaki Keita、Tedokon Iori、Morichika Kazuho、Nishi Yukiko、Tomoyose Takeaki、Karube Kennosuke、Fukushima Takuya、Murayama Sadayuki、Masuzaki Hiroaki
  • Journal Title: Hematology Volume: 22 Issue: 9 Pages: 536-543
  • DOI: 10.1080/10245332.2017.1312088
  • Peer Reviewed / Open Access
• [Presentation] がんの免疫回避とHLA. (2022)
  • Author(s): 森島聡子
  • Organizer: 第30回日本組織適合性学会大会
  • Invited
• [Presentation] Expression of HLA class II on HTLV-1 infected cells in patients with ATL and HTLV-1 carriers. (2022)
  • Author(s): 森島聡子, 椎名隆, 玉城啓太, 島袋康貴, 鈴木慎吾, 重成敦子, 宮城理子, 中島知,北村紗希子, 友利昌平, 花城多恵子, 森近一穂, 西由希子, 仲地佐和子, 福島卓也,益崎裕章
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] The impact of HLA expression level on transplant outcomes in HLA-matched UR-SCT. (2022)
  • Author(s): 森島聡子, 椎名隆, 森島泰雄, 東史啓, 友利昌平, 土岐典子, 小澤幸泰, 福田隆浩, 田中正嗣, 衛藤徹也, 河北敏郎, 荒隆英, 平本展大, 内田直之, 神田善伸, 諫田淳也, 鬼塚真仁, 一戸辰夫, 熱田由子, 村田誠
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] 遺伝子全領域の解析により明らかとなったATLに生じる多彩なHLA遺伝子異常 (2021)
  • Author(s): 森島聡子、玉城啓太、鈴木進悟、重成敦子、野村育美、横田雄太郎、森近一穂、西由希子、仲地佐和子、岡本士毅、福島卓也、椎名隆、益崎裕章
  • Organizer: 第7回日本HTLV-1学会学術集会
• [Presentation] A NGS-based high resolution typing elucidates novel perspectives on the HLA gene mutations in ATL. (2021)
  • Author(s): Tamaki K, Morishima S, Suzuki S, Shigenari A, Nomura I, Yokota Y, Morichika K, Nishi Y, Nakachi S, Okamoto S, Fukushima T, Shiina T, Masuzaki H.
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] The impact of individual HLAs on survival after allo-HSCT from HLA-matched donors for ATL patients. (2020)
  • Author(s): Morishima S, Shindo T, Utsunomiya A, Ishida T, Fukuda T, Nakano N, Sawayama Y, Miyamoto T, Ichinohe T, Atsuta Y, Yoshimitsu M, Kato K. Kawakita T, Eto T, Suehiro Y, Sawayama Y, Miyamoto T, Ichinohe T, Atsuta Y, Yoshimitsu M, Kato K.
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 造血細胞移植におけるHLAの意義 (2019)
  • Author(s): 森島 聡子
  • Organizer: 第81回日本血液学会学術集会
  • Invited
• [Presentation] Somatic Mutations and Loss of Heterozygosity of HLA Genes Are Frequently Occurred and Tightly Associated with Poor Prognosis in Adult T Cell Leukemia-Lymphoma. (2019)
  • Author(s): Tamaki K, Morishima S, Suzuki S, Shigenari A, Nomura I, Yokota Y, Morichika K, Nishi Y, Nakachi S, Okamoto S, Karube K, Fukushima T, Shiina T, Masuzaki H.
  • Organizer: 第61回米国血液学会
  • Int'l Joint Research
• [Presentation] 造血細胞移植に関わる新たなアロ免疫認識機構の解明 (2018)
  • Author(s): 森島 聡子
  • Organizer: 第27回日本組織適合性学会大会
• [Presentation] 非血縁者間骨髄移植における日本人の高頻度HLAハプロタイプ (HP-P2)の急性GVHD抑制効果 (2018)
  • Author(s): 森島聡子、東史啓、屋部登志雄、柏瀬貢一、椎名隆、加藤俊一、小寺良尚、笹月健彦、森島泰雄
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] Impact of mismatched HLA on graft-versus-host disease in unrelated stem cell transplantation. (2017)
  • Author(s): 森島聡子
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] JMDP HLA-DP study update -Evolutionary basis of HLA-DPB1 alleles affects acute GVHD in unrelated donor stem cell transplantation- (2017)
  • Author(s): Satoko Morishima
  • Organizer: The 17th International & Immunogenetics Workshop
  • Int'l Joint Research
• [Presentation] Validation study of prognostic indices and impact of strongyloidiasis for aggressive ATL in Okinawa (2017)
  • Author(s): 玉城啓太、森島聡子、野村尚吾、西由希子、仲地佐和子、北村紗希子、内堀幸恵、友利昌平、花城多恵子、島袋奈津紀、手登根伊織、森近一穂、平良直也、友寄毅昭、宮城敬、狩俣かおり、大濱昌代、山入端敦、玉城和光、林正樹、内原潤之介、大城一郁、朝倉義崇、宮良恵美、加留部謙之輔、福島卓也、益崎裕章
  • Organizer: 第79回日本血液学会学術集会