Mechanism of bone marrow failure in aplastic anemia -Role of mesenchymal stem cell-

• Project/Area Number: 19390283
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Nagoya University
• Principal Investigator: KOJIMA Seiji Nagoya University, 大学院・医学系研究科, 教授 (20313992)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Yoshiyuki 名古屋大学, 医学部・附属病院, 助教 (40432273) ; YAGASAKI Hirosi 名古屋大学, 大学院・医学系研究科, 助教 (90378141)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2008: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2007: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: 再生不良性貧血 / GATA-2 / 骨髄間葉系幹細胞 / PPARγ / 脂肪特異的転写因子

Research Abstract

再生不良性貧血(再不貧)患者由来の骨髄間葉系幹細胞(MSC)における、T細胞機能抑制能の低下はみられない。一方再不貧では、骨髄微小環境におけるIFN-γが増加していることから、血液幹細胞(HSC)におけるGATA-2の発現が低下している。GATA-2の発現低下は、HSCの分化増殖を障害して造血能を低下させるとともに、脂肪細胞特異的遺伝子であるPPARγの発現を増強し、骨髄の脂肪化をもたらすものと考えられる。

Research Products

• [Journal Article] Immunosuppressive activity of mesenchymal stem cells is not decreased in children with aplastic anemia (2009)
  • Author(s): Xu Y, Takahashi Y, Yoshimi A, Tanaka M, Yagasaki H, Kojima S.
  • Journal Title: Int J Hematol. 89 Pages: 126-127
  • NAID: 10025159958
• [Journal Article] Japanese Childhood AML Cooperative Study Group. Prospective multicenter trial comparing repeated immunosuppressive therapy with stem-cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia (2008)
  • Author(s): Kudo K, Kojima S, Tabuchi K, Yabe H, Tawa A, Imaizumi M, Hanada R, Hamamoto K, Kobayashi R, Morimoto A, Nakayama H, Tsuchida M, Horibe K, Kigasawa H, Tsukimoto I.
  • Journal Title: Blood 111 Pages: 1054-1059
• [Journal Article] Quantification of granulocyte-macrophage colony-stimulating factor hypersensitivity in juvenile myelomonocytic leukemia by 3H-thymidine assay (2008)
  • Author(s): Tanaka M, Takahashi Y, Xu Y, Yoshida N, Yoshimi A, Villalobos IB, Hama A, Nishio N, Hidaka H, Wang Y, Yagasaki H, Kojima S.
  • Journal Title: Leuk Res. 32 Pages: 1036-1042
• [Journal Article] Acute megakaryoblastic leukaemia (AMKL) in children: a comparison of AMKL with and without Down syndrome (2008)
  • Author(s): Hama A, Yagasaki H, Takahashi Y, Nishio N, Muramatsu H, Yoshida N, Tanaka M, Hidaka H, Watanabe N, Yoshimi A, Matsumoto K, Kudo K, Kato K, Horibe K, Kojima S.
  • Journal Title: Br J Haematol 140 Pages: 552-561
  • NAID: 120007138374
• [Journal Article] Japanese Childhood MDS Study Group. A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia (2008)
  • Author(s): Yabe M, Sako M, Yabe H, Osugi Y, Kurosawa H, Nara T, Tokuyama M, Adachi S, Kobayashi C, Yanagimachi M, Ohtsuka Y, Nakazawa Y, Ogawa C, Manabe A, Kojima S, Nakahata T
  • Journal Title: Pediatr Transplant 12 Pages: 862-867
• [Journal Article] Risk factors for early death in neonates with Down syndrome and transient leukaemia (2008)
  • Author(s): Muramatsu H, Kato K, Watanabe N, Matsumoto K, Nakamura T, Horikoshi Y, Mimaya J, Suzuki C, Hayakawa M, Kojima S.
  • Journal Title: Br J Haematol 142 Pages: 610-615
• [Journal Article] Clinical impact of HLA-DR15, a minor population of paroxysmal nocturnal haemoglobinuria -type cells, and an aplastic anaemia-associated autoantibody in children with acquired aplastic anaemia (2008)
  • Author(s): Yoshida N, Yagasaki H, Takahashi Y, Yamamoto T, Liang J, Wang Y, Tanaka M, Hama A, Nishio N, Kobayashi R, Hotta N, Asami K, Kikuta A, Fukushima T, Hirano N, Kojima S.
  • Journal Title: Br J Haematol Epub ahead of print
• [Journal Article] Japanese epidemiological survey with consensus statement on Japanese guidelines for treatment of iron overload in bone marrow failure syndromes (2008)
  • Author(s): Suzuki T, Tomonaga M, Miyazaki Y, Nakao S, Ohyashiki K, Matsumura I, Kohogo Y, Niitsu Y, Kojima S, Ozawa K.
  • Journal Title: Int J Hematol 88 Pages: 30-35
  • NAID: 10025159021
• [Journal Article] Japan Cord Blood Bank Network. Unrelated cord blood transplantation for severe aplastic anemia. Biol Blood Marrow Transplant (2008)
  • Author(s): Yoshimi A, Kojima S, Tanigushi S, Hara J, Matsui T, Takahashi Y, Azuma H, Kato K, Nagamura-Inoue T, Kai S, Kato S
  • Journal Title: Biol Blood Marrow Transplant 14 Pages: 1057-1063
• [Journal Article] Congenital erythroid and myeloid hypoplasia terminating myelodysplastic syndrome (2008)
  • Author(s): Nishio N, Yagasaki Y, Takahashi Y, Muramatsu H, Hama A, Zu Y, Villalobos IB, Kojima S.
  • Journal Title: J Pediatr Hematol Oncol 30 Pages: 692-695
• [Journal Article] Outcome of bone marrow transplantation from HLA-identical sibling donor in children with hematological malignancies using methotrexate alone as prophylaxis for graft-versus-host disease (2008)
  • Author(s): Watanabe N, Matsumoto K, Yoshimi A, Horibe K, Matsuyama T, Kojima S, Kato K.
  • Journal Title: Int J Hematol 88 Pages: 575-582
  • NAID: 10023971436
• [Journal Article] Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia (2008)
  • Author(s): Yoshida N, Yagasaki H, Xu Y, Matsuda K, Yoshimi A, Takahashi Y, Hama A, Nishio N, Muramatsu H, Watanabe N, Matsumoto K, Kato K, Ueyama J, Inada H, Goto H, Yabe M, Kudo K, Miyama J, Kikushi A, Manabe A, Koike K, Kojima S.
  • Journal Title: Pediatr Res. [Epub ahead of print]
• [Journal Article] Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children (2008)
  • Author(s): Nishio N, Yagasaki H, Takahashi Y, Hama A, Muramatsu H, Tanaka M, Yoshida N, Yoshimi A, Kudo K, Ito M, Kojima S.
  • Journal Title: Pediatr Transplant [Epub ahead of print]
• [Journal Article] Prospective multicenter trial comparing repeated immunosuppre ssive therapy with stem-cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia. (2008)
  • Author(s): Kosaka Y, Kojima S, et al.
  • Journal Title: Blood 111 Pages: 1054-1059
  • Peer Reviewed
• [Journal Article] Acute megakaryoblastic leukaemia (AMKL) in children : a comparison of AMKL with and without Down syndrorae. (2008)
  • Author(s): Hama A, Kojima S, et al
  • Journal Title: Br J Haematol 140 Pages: 552-661
  • Peer Reviewed
• [Journal Article] Quantification of granulocyte-macrophage colony-stimulating factor hypersensitivity in juvenile myelomonocytic leukemia by 3H-thymidine assay. (2008)
  • Author(s): Tanaka M, Kojima S, et al.
  • Journal Title: Leuk Res 32 Pages: 1036-1042
  • Peer Reviewed
• [Journal Article] Functional analysis of JAK3 mutations in transient myeloprolif erative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome. (2008)
  • Author(s): Sato T, Kojima S, et al.
  • Journal Title: Br J Haematol 141 Pages: 681-688
  • Peer Reviewed
• [Journal Article] A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia. (2008)
  • Author(s): Yabe M, Koiima S, et al.
  • Journal Title: Pediatr Transplant 12 Pages: 862-867
  • Peer Reviewed
• [Journal Article] Congenital erythroid and myeloid hypoplasia terminating myelo dysplastic syndrome. (2008)
  • Author(s): Nishio N, Kojima S, et al.
  • Journal Title: J Pediatr Hematol Oncol 30 Pages: 692-695
  • Peer Reviewed
• [Journal Article] Unrelated cord blood transplantation for severe aplastic anemia (2008)
  • Author(s): Yoshimi A, Kojima S, et al.
  • Journal Title: Biol Blood Marrow Transplant 14 Pages: 1057-1063
  • Peer Reviewed
• [Journal Article] Japanese epidemiological survey with consensus statement on Japanese guidelines for treatment of iron overload in bone marrow failure syndromes. (2008)
  • Author(s): Suzuki T, Kojima S, et al.
  • Journal Title: Int J Hematol 88 Pages: 30-35
  • NAID: 10025159021
  • Peer Reviewed
• [Journal Article] Clinical impact of HLA-DR15, a minor population of paroxysmal nocturnal haemoglobinuria-type cells, and an aplastic anaemia-associated autoantibody in children with acquired aplastic anaemia. (2008)
  • Author(s): Yoshida N, Kojima S, et al.
  • Journal Title: Br J Haematol 3
  • Peer Reviewed
• [Journal Article] Risk factors for early death in neonates with Down syndrome and transient leukaemia. (2008)
  • Author(s): Muramatsu H, Kojima S, et al.
  • Journal Title: Br J Haematol 142 Pages: 610-615
  • Peer Reviewed
• [Journal Article] Engraftment syndrome following allogeneic hematopoietic stem cell transplantation in children. (2008)
  • Author(s): Nishio N, Kojima S, et al.
  • Journal Title: Pediatr Transplant 1
  • Peer Reviewed
• [Journal Article] Correlation of clinical features with the mutational status of G M-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. (2008)
  • Author(s): Yoshida N, Kojima S, et al.
  • Journal Title: Pediatr Res 26
  • Peer Reviewed
• [Journal Article] Mutational analysis of SOS1 gene in acute myeloid leukemia. (2008)
  • Author(s): Tanizaki R, Kojima S, etal.
  • Journal Title: Int J Hematol 88 Pages: 460-462
  • NAID: 10023970986
  • Peer Reviewed
• [Journal Article] Prospective multicenter trial comparing repeated immunosuppressive therapy with stem cell transplantation from an alternative donor as second-line treatment for with severe and very severe aplastic anemia. (2008)
  • Author(s): Kosaka Y, Kojima S, et. al.
  • Journal Title: Blood 111 Pages: 1054-1059
  • Peer Reviewed
• [Journal Article] Increased midkine gene expression in childhood B-precursor acute lymphoblastic leukemia. (2008)
  • Author(s): Hidaka H, Kojima S, et. al.
  • Journal Title: Leukemia Research 31 Pages: 1045-1051
  • Peer Reviewed
• [Journal Article] Pro-inflammatory cytokinemia is frequently found in Down syndrome patients with hematological disorders. (2008)
  • Author(s): Shimada A, Kojima S, et. al.
  • Journal Title: Leukemia Research 31 Pages: 1199-1203
  • Peer Reviewed
• [Journal Article] Increased midkine gene expression in childhood B-precursor acute lymphoblastic leukemia (2007)
  • Author(s): Hidaka M, Yagasaki H, Takahashi Y, Hama A, Nishio N, Tanaka M, Yoshida N, Villalobos IB, Wang Y, Xu Y, Horibe K, Dhen S, Kadomatsu K, Kojima S.
  • Journal Title: Leuk Res. 83 Pages: 535-540
• [Journal Article] Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations (2007)
  • Author(s): Matsuda K, Shimada A, Yoshida N, Ogawa A ,Watanabe A, Yajima S, Iizuka S, Koike K, Yanai F, Kawasaki K, Yanagimachi M, Kikushi A, Ohtsuka Y, Hidaka E, Yamaguchi K, Tanaka M, Yanagisawa R, Nakazawa Y, Shiohara M, Manabe A, Kojima S.
  • Journal Title: Blood 109 Pages: 544-544
• [Journal Article] Feasibility and results of bone marrow transplantation from an HLA-mismatched unrelated donor for children and young adults with acquired severe aplastic anemia (2007)
  • Author(s): Yagasaki H, Takahashi Y, Kudo K, Ohashi H, Hama A, Yamamoto T, Tanaka M, Yoshida N, Hidaka H, Nishio N, Kojima S.
  • Journal Title: Int J Haematol 85 Pages: 437-442
• [Journal Article] Mutation of SBDS and SH2D1A is not associated with aplastic anemia in Japanese children (2007)
  • Author(s): Wang Y, Yagasaki H, Hama A, Nishio N, Takahashi Y, Kojima S.
  • Journal Title: Haematologica 92 Pages: 1573-1573
• [Journal Article] Japanese Childhood AML Cooperative Study Group. Prospective study of a pirarubicin, intermediate-dose cytarabine, and etoposide regimen in children with Down syndrome and acute myeloid leukemia: the Japanese Childhood AML Cooperative Study Group (2007)
  • Author(s): Kudo K, Kojima S, Tabuchi K, Yabe H, Tawa A, Imaizumi M, Hanada R, Hamamoto K, Kobayashi R, Morimoto A, Nakayama H, Tsuchida M, Horibe K, Kigasawa H, Tsukimoto I
  • Journal Title: J Clin Oncol 25 Pages: 5442-5447
• [Journal Article] Japan Childhood Aplastic Anemia Study Group. Antithymocyte globulin and cyclosporine for treatment of 44 children with hepatitis associated aplastic anemia (2007)
  • Author(s): Osugi Y, Yagasaki H, Sako M, Kosaka Y, Taga T, Ito T, Yamamoto M, Ohara A, Sato T, Mimaya J, Tsukimoto I, Kojima S
  • Journal Title: Haematologica 92 Pages: 1687-1690
• [Journal Article] Prospective study of a pirarubicin, intermediate-dose cytarabine and etoposide regimen in children with Down syndrome and acute myeloid leukemia. (2007)
  • Author(s): Kudo K, Kojima S, et. al.
  • Journal Title: J Cli Oncol 25 Pages: 5442-5447
  • Peer Reviewed
• [Journal Article] Antithymocyte globulin and cyclosporine for treatment of 44 children with hepatitis associated aplastic anemia. (2007)
  • Author(s): Osugi Y, Kojima S, et. al.
  • Journal Title: Haematologica 92 Pages: 1687-1690
  • Peer Reviewed
• [Journal Article] Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. (2007)
  • Author(s): Matsuda K, Kojima S, et. al.
  • Journal Title: Blood 109 Pages: 5477-5480
  • Peer Reviewed
• [Presentation] 再生不良性貧血における造血障害機序 : IFN-γは骨髄間葉系幹細胞のGATA-2の発現を低下させる (2008)
  • Author(s): 徐銀燕, 小島勢二, 他
  • Organizer: 日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-11
• [Presentation] Bone Marrow Transplantation for Children with chronic myeloid leukemia (CML): A Report from the Japan Marrow Donor Program (JMDP) (2008)
  • Author(s): Muramatsu H, Kojima S, et. al.
  • Organizer: 50th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Predicting response to immunosuppressive therapy in childhood aplastic anemia (2008)
  • Author(s): Yoshida N, Kojima S, et. al.
  • Organizer: 50th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Gene alterations and expression of hematopoietic transcription factors in pediatric acute megakaryobblastic leukemia (AMKL): A Comparison of Down Syndrome (DS)-associated AMKL with Non-DS-AMKL (2008)
  • Author(s): Hama A, Kojima S, et. al.
  • Organizer: 50th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Myelodysplastic Syndrome (MDS) and myeloproliferative disease (MPD) in children: A Prospective registrarion of 222 Cases (2008)
  • Author(s): Manabe A, Kojima S, et. al.
  • Organizer: 50th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Mismatching at HLA-DPB1 is Not associated with survival in patients with acquired aplastic anemia who receive unrelated bone marrow transplantation (2008)
  • Author(s): Yagasaki H, Kojima S, et. al.
  • Organizer: 50th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Relapse of children with aplastic anemia after immunosuppressive therapy (2008)
  • Author(s): Kamati Y, Kojima S, et. al.
  • Organizer: 50th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Improved outcome of unrelated bone marrow transplantation for severe aplastic anemia (2008)
  • Author(s): Yagasaki H, Kojima S, et. al.
  • Organizer: 49th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Should hematopoietic stem cell transplantation in first complete remission be restricted to high-risk patients in childhood acute myeloid leukemia (2008)
  • Author(s): Muramatsu H, Kojima S, et. al.
  • Organizer: 49th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] JAK3, JAK2 and GATA1 mutations in childhood acute megakaryoblastic leukemia with and without down syndrom (2008)
  • Author(s): Hama A, Kojima S, et. al.
  • Organizer: 49th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Decreased incidence of clonal evolution to myelodysplastic syndrome/ acute myeloid leukemia with monosomy7 in children with aplastic anemia following reduced use of G-CSF (2008)
  • Author(s): Takahashi Y, Kojima S, et. al.
  • Organizer: 49th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Natural History of Transfusion-independent non-Severe Aplastic Anemia in Children (2008)
  • Author(s): Nishio N, Kojima S, et. al.
  • Organizer: 49th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Correlation of clinical features with the mutational status of GM-CSF signaling Pathway-related genes in children with juvenile myelomonocytic leukemia (2008)
  • Author(s): Yoshida N, Kojima S, et. al.
  • Organizer: 49th Annual Meeting of the American Society of Hematology
  • Place of Presentation: Atlanta USA
• [Presentation] Therapeutic strategies and clinical results in JMML-Update on Japanese trial (2008)
  • Author(s): Kojima S
  • Organizer: 2nd JMMLsymposium
  • Place of Presentation: Atlanta USA
• [Presentation] 再生不良性貧血の造血障害機序-骨髄間葉系細胞の関与 (2007)
  • Author(s): 徐銀燕、小島勢二, 他
  • Organizer: 日本血液学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-12
• [Book] 小児科第3版 (2008)
  • Author(s): 小島勢二, 他
  • Publisher: 医学書院
• [Book] 小児科診療ガイドライン-最新の診療指針- (2007)
  • Author(s): 小島勢二, 他
  • Publisher: 総合医学社