Identification of cytokines responsible for the development of immune-mediated bone marrow failure using gene expression analyses of patients with aplastic anemia

• Project/Area Number: 25670448
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: NAKAO Shinji 金沢大学, 医学系, 教授 (70217660)
• Co-Investigator(Renkei-kenkyūsha): OGAWA Seishi 京都大学, 医学(系)研究科(研究院), 教授 (60292900)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 再生不良性貧血 / 造血抑制性サイトカイン / インターロイキン１０ / CXCL12 / クローン性造血 / マイクロアレイ / 発作性夜間血色素尿症 / ゲノム変異 / NFAT / Nr4a / シクロスポリン / エクソームシーケンシング

Outline of Final Research Achievements

In an attempt to identify cytokines responsible for the development of immune-mediated bone marrow failure, we determined gene expression profiles of peripheral blood leukocytes from eight untreated patients with non-severe aplastic anemia who had not been transfused. Expressions of several genes associated with erythropoiesis as well as signaling pathways involved in the expression of IL10 and CXCL12 were found to be augmented. Whole exome sequencing of peripheral blood leukocytes from 12 aplastic anemia patients who obtained a complete remission after immunosuppressive therapy revealed somatic mutations of genes related to hematopoietic stem cell quiescence such as PEG3 and SMARCA2.

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
• [Presentation] Hematopoiesis in Patients with Acquired Aplastic Anemia Is Supported By a Limited Number of CXCR4(-) Cells at the Common Myeloid Progenitor Level (2014)
  • Author(s): Takamasa Katagiri, PhD*,1, Atsuo Kasada, MD*,2, Kana Motomiya, MD*,3, Yoshitaka Zaimoku, MD*,3, An T. T. Dao, MD*,3, Hiroyuki Maruyama, MD*,3, Ken Ishiyama, MD, PhD*,3, Shigeki Ohtake, MD PhD1, Atsushi Hirao, MD2, and Shinji Nakao, MD PhD
  • Organizer: The American Society of Hematology 56th Annual Meeting
  • Place of Presentation: Francisco, California, USA.
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] IncreasedHigh gene expression of Nr4A family in bone marrow T cells is associated with rapid response after ISTto cyclosoporine in the patients with non-severeearly stage acuired aplastic anemia (2013)
  • Author(s): Kohei Hosokawa, Takumi Nishiuchi, Takamasa Katagiri, Chizuru Saito, Hiroyuki Maruyama, Naomi Sugimori, Hirohito Yamazaki, Shinji Nakao
  • Organizer: 第55回アメリカ血液学会年次集会
  • Place of Presentation: Ernest N.Morial Convention Center,New Orleans,LA USA