Development of a new therapy targeting CXCR4+ hematopoietic stem cells in patients with bone marrow failure

• Project/Area Number: 15K15360
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: Shinji Nakao 金沢大学, 医学系, 教授 (70217660)
• Co-Investigator(Renkei-kenkyūsha): Yoshida Yoshinori 京都大学, iPS細胞研究所, 講師 (20447965) ; Nishiuchi Takumi 金沢大学, 学際科学実験センター, 准教授 (20334790)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 再生不良性貧血 / 造血幹前駆細胞 / CXCR4 / BRGSマウス / iPS細胞 / 6pLOH / CD34陽性細胞 / CXCL12 / 造血幹細胞 / 造血前駆細胞

Outline of Final Research Achievements

A chemokine receptor CXCR4 is preferentially expressed by redundant hematopoietic stem/progenitor cells (HSPCs) that do not contribute to hematopoiesis. Stimulation of residual CXCR4(+) HSPCs may restore hematopoietic function of patients with acquired aplastic anemia (AA). First, we optimized method of engrafting an immune-deficient mouse (BRGS mouse) with cord-blood CD34(+) cells using intra-bone marrow injection, and confirmed the presence of human CD45(+) cells that accounted for 3.3-20.4% of the various tissue-derived cells. Next, we induced HSPCs from iPS cells that were generated from monocytes of AA patients possessing 6pLOH(+) leukocytes, which were predominant in the patients’ blood, as a result of uniparental disomy, and injected the HSPCs to the same mice. Regenerating human 6pLOH(+)CD34(+) cells in the mice expressed CXCR4 to a significantly lesser degree (mean 10.2%) than did 6pLOH(-)CD34(+) cells. We are currently exploring a method to activate CXCR4(+) HSPCs in vivo.

Research Products

• [Journal Article] Identification of an HLA class I allele closely involved in the auto-antigen presentation in acquired aplastic anemia. (2017)
  • Author(s): Zaimoku Y, Takamatsu H, Hosomichi K, Ozawa T, Nakagawa N, Imi T, Maruyama H, Katagiri T, Kishi H, Tajima A, Muraguchi A, Kashiwase K, Nakao S.
  • Journal Title: Blood Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Induction of HLA-B*40:02-restricted T cells possessing cytotoxic and suppressive functions against haematopoietic progenitor cells from a patient with severe aplastic anaemia. (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: in press Issue: 1 Pages: 131-134
  • DOI: 10.1111/bjh.13464
  • Peer Reviewed / Acknowledgement Compliant
• [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 CO, 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 Engl J Med. Volume: 373 Issue: 1 Pages: 35-47
  • DOI: 10.1056/nejmoa1414799
  • NAID: 120005623244
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Paroxysmal nocturnal hemoglobinuria induced by the occurrence of BCR-ABL in a PIGA mutant hematopoietic progenitor cell. (2015)
  • Author(s): Tominaga R, Katagiri T, Kataoka K, Wee RK, Maeda A, Gomyo H, Mizuno I, Murayama T, Ogawa S, Nakao S.
  • Journal Title: Leukemia. Volume: - Issue: 5 Pages: 1208-1210
  • DOI: 10.1038/leu.2015.268
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Relatively Low Sensitivity of CD109(-) Hematopoietic Stem/Progenitor Cells (HSPCs) to TGF-β: A Possible Mechanism Responsible for the Preferential Commitment of Piga Mutant HSPCs in Immune-Mediated Bone Marrow Failure (2016)
  • Author(s): Noriharu Nakagawa
  • Organizer: The American Society of Hematology 58th Annual Meeting
  • Place of Presentation: San Diego Convention Center, Hall GH
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] HLA Class I Allele-Lacking Hematopoietic Stem/Progenitor Cells Support Long-Term Clonal Hematopoiesis without Oncogenic Driver Mutations in Acquired Aplastic Anemia. (2016)
  • Author(s): Tatsuya Imi
  • Organizer: The American Society of Hematology 58th Annual Meeting
  • Place of Presentation: San Diego Convention Center, Hall GH
  • Year and Date: 2016-12-03
  • Int'l Joint Research