Identification of myelosuppressive cytokines taking advantage of genomic abnormalities of leukocytes in patients with aplastic anemia

• Project/Area Number: 24390243
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: NAKAO Shinji 金沢大学, 医学系, 教授 (70217660)
• Co-Investigator(Kenkyū-buntansha): AKATSUKA Yoshiki 藤田保健衛生大学, 医学部, 教授 (70333391)
• Co-Investigator(Renkei-kenkyūsha): MATSUI Hirotaka 広島大学, 原爆放射線医科学研究所, 准教授 (60379849) ; TAKAMATSU Hiroyuki 金沢大学, 医学系, 助教 (70401932) ; NISHIUCHI Takumi 金沢大学, 学際科学実験センター, 准教授 (20334790)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2012: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: 再生不良性貧血 / クロナリティ / 免疫抑制療法 / 細胞傷害性T細胞 / 片親性二倍体 / クローン性造血 / ゲノム変異 / 6pUPD / SLIT1 / CD109 / HLA-B*40:02 / HLA-Aアレル欠失血球 / エスケープ造血 / 可溶性HLAペプチドーム

Outline of Final Research Achievements

To determine genomic abnormalities responsible for clonal hematopoiesis in patients with aplastic anemia (AA), we analyzed peripheral blood DNA from 159 patients with aplastic anemia using a next generation sequencer. At least one gene abnormality was detectable in approximately 40% of the patient. Recurrent abnormalities included those of DNMT3 and ASXL1 that were often detected in patients with myelodysplastic syndrome (MDS). However, the presence of PIGA and BCOR/BCOR1 abnormalities were rather associated with good response to immunosuppressive therapy than the risk of evolving into MDS. In another attempt to clarify the immune mechanism of AA, we successfully isolated a cytotoxic T cell clone from an AA patient with uniparental disomy of chromosome 6p, which killed hematopoietic progenitor cells in a resitricted manner by HLA-DRB1*40:02.

Research Products

• [Journal Article] Somatic mutations and clonal hematopoiesis in aplastic anemia (2015)
  • Author(s): Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, Sato-Otsubo A, Sato Y, Liu D, Suzuki H, Wu C, Shiraishi Y, Clemente MJ, Kataoka K, Shiozawa Y, Okuno Y, Chiba K, Tanaka H, Nagata Y, Katagiri T, Kon A, Sanada M, Scheinberg P, Miyano S, Maciejewski JP, Nakao S, Young NS, Ogawa S.
  • Journal Title: N Eng J Med Volume: -
  • NAID: 120005623244
  • Peer Reviewed
• [Journal Article] Induction of HLA-B*40:02-restricted T cells possessing cytotoxic and suppressive functions against hematopoietic progenitor cells from a patient with severe aplastic anemia. (2015)
  • Author(s): Inaguma Y, Akatsuka Y, Hosokawa K, Maruyama H, Okamoto A, Katagiri T, Shiraishi K, Murayama Y, Tsuzuki-Iba S, Mizutani Y, Nishii C, Yamamoto N, Demachi-Okamura A, Kuzushima K, Ogawa S, Emi N, Nakao S.
  • Journal Title: Br J Haematol Volume: -
  • Peer Reviewed
• [Journal Article] Imatinib for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. (2015)
  • Author(s): Watanabe S, Waseda Y, Kimura H, Takato H, Ohata K, Kondo Y, Kasahara K, Nakao S.
  • Journal Title: Bone Marrow Transplant Volume: -
  • Peer Reviewed
• [Journal Article] Persistent molecular remission of refractory acute myeloid leukemia with inv(16)(p13.1q22) in an elderly patient induced by cytarabine ocfosfate hydrate. (2015)
  • Author(s): Arahata M, Shimizu Y, Asakura H, Nakao S.
  • Journal Title: J Hematol Oncol Volume: - Issue: 1 Pages: 5-5
  • DOI: 10.1186/s13045-014-0100-6
  • Peer Reviewed / Open Access
• [Journal Article] Paraptosis cell death induction by the thiamine analog benfotiamine in leukemia cells. (2015)
  • Author(s): Sugimori N, Espinoza JL, Trung LQ, Takami A, Kondo Y, An DT, Sasaki M, Wakayama T, Nakao S.
  • Journal Title: PloS One Volume: - Issue: 4 Pages: e0120709-e0120709
  • DOI: 10.1371/journal.pone.0120709
  • Peer Reviewed / Open Access
• [Journal Article] Increased glycosylphosphatidylinositol-anchored protein-deficient granulocytes define a benign subset of bone marrow failures in patients with trisomy 8. (2014)
  • Author(s): Hosokawa K, Sugimori N, Katagiri T, Sasaki Y, Saito C, Seiki Y, Mochizuki K, Yamazaki H, Takami A, Nakao S.
  • Journal Title: Eur J Haemat Volume: 18 Issue: 3 Pages: 230-238
  • DOI: 10.1111/ejh.12484
  • NAID: 120005661927
  • Peer Reviewed / Open Access
• [Journal Article] Relative incidences and outcomes of Clostridium difficile infection following transplantation of unrelated cord blood, unrelated bone marrow, and related peripheral blood in adult patients: a single institute study. (2014)
  • Author(s): Hosokawa K, Takami A, Tsuji M, Araoka H, Ishiwata K, Takagi S, Yamamoto H, Asano-Mori Y, Matsuno N, Uchida N, Masuoka K, Wake A, Makino S, Yoneyama A, Nakao S, Taniguchi S.
  • Journal Title: Transp Infectious Dis Volume: 16 Issue: 3 Pages: 412-420
  • DOI: 10.1111/tid.12224
  • Peer Reviewed / Open Access
• [Journal Article] Successful hyperbaric oxygen therapy for refractory BK virus-associated hemorrhagic cystitis after cord blood transplantation. (2014)
  • Author(s): Hosokawa K, Yamazaki H, Nakamura T, Yoroidaka T, Imi T, Shima Y, Ohata K, Takamatsu H, Kotani T, Kondo Y, Takami A, Nakao S.
  • Journal Title: Transp Infectious Dis Volume: 16 Issue: 5 Pages: 843-846
  • DOI: 10.1111/tid.12266
  • Peer Reviewed / Open Access
• [Journal Article] Individual hematopoietic stem cells in human bone marrow of patients with aplastic anemia or myelodysplastic syndrome stably give rise to limited cell lineages. (2013)
  • Author(s): Katagiri T, et al.
  • Journal Title: Stem Cells Volume: 31 Issue: 3 Pages: 536-46
  • DOI: 10.1002/stem.1301
  • Peer Reviewed
• [Journal Article] Increased plasma thrombopoietin levels in patients with myelodysplastic syndrome: a reliable marker for a benign subset of bone marrow failure. (2013)
  • Author(s): Seiki Y, et al.
  • Journal Title: Haematologica Volume: (in press)
  • Peer Reviewed
• [Journal Article] Favorable outcome of patients who have 13q deletion: a suggestion for revision of the WHO 'MDS-U' designation. (2012)
  • Author(s): Hosokawa K, et al.
  • Journal Title: Haematologica Volume: 97 Issue: 12 Pages: 1845-9
  • DOI: 10.3324/haematol.2011.061127
  • Peer Reviewed
• [Presentation] Evidence that HLA-B*40:02 and HLA-Α*31:01 are strongly involved in the presentation of autoantigens to CTLs responsible for the development of acquired aplastic anemia (2014)
  • Author(s): Yoshitaka Zaimoku, Hiroyuki Maruyama, Kana Maruyama, Takamasa Katagiri, An T. T. Dao, Hiroyuki Takamatsu, Hirohito Yamazaki, Koichi Kashiwase and Shinji Nakao
  • Organizer: The American Society of Hematology 56th Annual Meeting
  • Place of Presentation: Moscone Center, San Francisco, California, USA.
  • Year and Date: 2014-12-07
• [Presentation] SLIT1 mutation in patients with acquired aplastic anemia : Its relevance in immune pathophysiology. (2012)
  • Author(s): Chizuru Saito
  • Organizer: The American Society of Hematology 54th Annual Meeting,
  • Place of Presentation: GEORGIA WORLD CONGRESS CENTER Atlanta, Georgia, USA.
  • Year and Date: 2012-12-10
• [Presentation] Detection of leukocytes lacking HLA-A alleles by flow cytometry predicts a response to immunosuppressive therapy in patients with acquired aplastic anemia.
  • Author(s): Hiroyuki Maruyama, Takamasa Katagiri, Kohei Hosokawa, Chizuru Saito, Hirohito Yamazaki, Shinji Nakao
  • Organizer: European Group for Blood and Marrow Transplantation
  • Place of Presentation: ExCel London One Western Gateway Royal Victoria Dock london,UK