Targeting cancer stem cells in myelodysplastic syndrome

• Project/Area Number: 23591392
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kyushu University
• Principal Investigator: TAKENAKA Katsuto 九州大学, 大学病院, 講師 (30301295)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 骨髄異形成症候群 / がん幹細胞 / 免疫不全マウス / 異種移植アッセイ / SIRPA / 幹細胞 / 異種移植モデル

Research Abstract

Cancer stem cells (CSCs) are therapeutic targets and must be eliminated to cure the patients. However, those cells have not been found yet in myelodysplastic syndrome (MDS). Immunodeficient mice are widely used to reconstitute human hematopoiesis by xenotransplantation of hematopoietic stem cells (HSCs), and this model provides a powerful tool to evaluate biological properties of human cancer stem cells. We found that in xenograft rejection, the innate phagocytic reaction of mouse macrophages could occur because murine SIRPA (mSIRPA) on macrophages cannot bind to human CD47 (hCD47). Thus, introduction of human SIRPA allows mouse macrophage to bind hCD47 on the graft, resulting in inhibition of phagocytic reaction against human cells. Here, we have established a new immunodeficient mouse line, B6-Rag2(null)Il2rg(null) mice with human SIRPA to induce complete macrophage tolerance.This strain should be very useful in xenotransplant experiments to assay MDS stem cells.

Research Products

• [Journal Article] The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment (2014)
  • Author(s): Iwamoto C, Takenaka K,以下14名
  • Journal Title: Exp Hematol Volume: 42(3) Pages: 163-71
• [Journal Article] The BALB/c-specific polymorphic SIRPA enhances its affinity for human CD47, inhibiting phagocytosis against human cells to promote xenogeneic engraftment. (2014)
  • Author(s): Iwamoto C, Takenaka K, Urata S, Yamauchi T, Shima T, Kuriyama T, Daitoku S, Saito Y, Miyamoto T, Iwasaki H, Kitabayashi I, Itoh K, Kishimoto J, Kohda D, Matozaki T, Akashi K.
  • Journal Title: Exp Hematol Volume: 42 Pages: 163-171
  • Peer Reviewed
• [Journal Article] Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment (2013)
  • Author(s): Yamauchi T, Takenaka ,以下12名
  • Journal Title: Blood Volume: 121(8) Pages: 1316-25
  • NAID: 40019873170
• [Journal Article] Contribution of bone marrow-derived hematopoietic stem/progenitor cells to the generation of donor-marker(+) cardiomyocytes in vivo (2013)
  • Author(s): Fukata M,以下14名
  • Journal Title: PLoS One Volume: 8(5)
• [Journal Article] Quantitation of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic hematopoietic stem cell transplantation (2013)
  • Author(s): Shima T,以下16名
  • Journal Title: Blood Volume: 121(5) Pages: 840-8
• [Journal Article] Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. (2013)
  • Author(s): Yamauchi T, Takenaka K, Urata S, Shima T, Kikushige Y, Tokuyama T, Iwamoto C, Nishihara M, Iwasaki H, Miyamoto T, Honma N, Nakao M, Matozaki T, Akashi K.
  • Journal Title: Blood Volume: 121 Pages: 1316-25
  • NAID: 40019873170
  • Peer Reviewed
• [Journal Article] Quantitation of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic hematopoietic stem cell transplantation. (2013)
  • Author(s): Shima T, Miyamoto T, Kikushige Y, Mori Y, Kamezaki K, Takase K, Henzan H, Numata A, Ito Y, Takenaka K, Iwasaki H, Kamimura T, Eto T, Nagafuji K, Teshima T, Kato K, Akashi K.
  • Journal Title: Blood Volume: 121 Pages: 840-8
  • Peer Reviewed
• [Journal Article] Contribution of bone marrow-derived hematopoietic stem/progenitor cells to the generation of donor-marker⁺ cardiomyocytes in vivo. (2013)
  • Author(s): Fukata M, Ishikawa F, Najima Y, Yamauchi T, Saito Y, Takenaka K, Miyawaki K, Shimazu H, Shimoda K, Kanemaru T, Nakamura K, Odashiro K, Nagafuji K, Harada M, Akashi K.
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Quantitation of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic hematopoietic stem cell transplantation. (2013)
  • Author(s): Shima T, Miyamoto T, Kikushige Y, Mori Y, Kamezaki K, Takase K, Henzan H, Numata A, Ito Y, Takenaka K, Iwasaki H, Kamimura T, Eto T, Nagafuji K, Teshima T, Kato K, Akashi K
  • Journal Title: Blood Volume: 121 Pages: 840-848
  • Peer Reviewed
• [Journal Article] Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment. (2013)
  • Author(s): Yamauchi T, Takenaka K, Urata S, Shima T, Kikushige Y, Tokuyama T, Iwamoto C, Nishihara M, Iwasaki H, Miyamoto T, Honma N, Nakao M, Matozaki T, Akashi K
  • Journal Title: Blood Volume: 121 Pages: 1316-1325
  • NAID: 40019873170
  • Peer Reviewed
• [Journal Article] Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis (2012)
  • Author(s): Kuriyama T, Takenaka K,以下12名
  • Journal Title: Blood Volume: 120(19) Pages: 4058-67
• [Journal Article] Initial low-dose valganciclovir as a preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients (2012)
  • Author(s): Takenaka K,以下13名
  • Journal Title: Int J Hematol Volume: 96(1) Pages: 94-100
  • NAID: 10030954633
• [Journal Article] Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis. (2012)
  • Author(s): Kuriyama T, Takenaka K, Kohno K, Yamauchi T, Daitoku S, Yoshimoto G, Kikushige Y, Kishimoto J, Abe Y, Harada N, Miyamoto T, Iwasaki H, Teshima T, Akashi K
  • Journal Title: Blood Volume: 120 Pages: 4058-4067
  • Peer Reviewed
• [Journal Article] 白血病幹細胞 (2012)
  • Author(s): 竹中克斗、赤司浩一
  • Journal Title: 日本臨床 Volume: 70 suppl 2 Pages: 139-145
• [Journal Article] 骨髄不全症候群 (2012)
  • Author(s): 竹中克斗
  • Journal Title: 日本内科学会雑誌 Volume: 101 Pages: 1969-1946
• [Journal Article] Initial low-dose valganciclovir as a preemptive therapy is effective for cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients. (2012)
  • Author(s): Takenaka K, Nagafuji K, Takase K, Kamimura T, Mori Y, Ito Y, Nishi Y, Henzan H, Kato K, Harada N, Eto T, Miyamoto T, Teshima T, Akashi K.
  • Journal Title: Int J Hematol Volume: 96 Pages: 94-100
  • NAID: 10030954633
  • Peer Reviewed
• [Journal Article] Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia (2011)
  • Author(s): Kikushige Y,以下13名
  • Journal Title: Cancer Cell Volume: 20(2) Pages: 246-59
• [Journal Article] Stem cell gene expression programs influence clinical outcome in human leukemia (2011)
  • Author(s): Eppert K, Takenaka K,以下17名
  • Journal Title: Nat Med Volume: 17(9) Pages: 1086-93
• [Journal Article] Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia (2011)
  • Author(s): Kikushige Y, Ishikawa F, Miyamoto T, Shima T, Urata S, Yoshimoto G, Mori Y, Iino T, Yamauchi T, Eto T, Niiro H, Iwasaki H, Takenaka K, Akashi K
  • Journal Title: Cancer Cell Volume: 20 Pages: 246-259
  • Peer Reviewed
• [Journal Article] Stem cell gene expression programs influence clinical outcome in human leukemia (2011)
  • Author(s): Eppert K, Takenaka K, Lechman ER, et
  • Journal Title: Nat Med Volume: 17 Pages: 1086-1093
  • Peer Reviewed
• [Presentation] Cytomegalovirus reactivation after allogeneic stem cell transplantation is associated with a reduced risk of relapse in patients with acute myeloid leukemia (2013)
  • Author(s): Katsuto Takenaka
  • Organizer: 第55回米国血液学会
  • Place of Presentation: ニューオリンズ、米国
  • Year and Date: 2013-12-10
• [Presentation] BALB/c- specific L29V polymorphism in SIRPA determines the efficient engraftment of human hematopoiesis in xenogeneic model (2013)
  • Author(s): Iwamoto C, Takenaka K, et al
  • Organizer: 第55回米国血液学会
  • Place of Presentation: ニューオリンズ、米国
  • Year and Date: 2013-12-09
• [Presentation] Fibrotic tissues in human primary myelofibrosis with JAK2 V617F are developed clonally from malignant hematopoietic stem cells (2013)
  • Author(s): amauchi T, Shima T, Takenaka K, et al
  • Organizer: 第55回米国血液学会
  • Place of Presentation: ニューオリンズ、米国
  • Year and Date: 2013-12-08
• [Presentation] 教育講演48 移植後のウイルス感染症 (2013)
  • Author(s): 竹中克斗
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌市
  • Invited
• [Presentation] Cytomegalovirus Reactivation After Allogeneic Stem Cell Transplantation Is Associated With a Reduced Risk Of Relapse In Patients With Acute Myeloid Leukemia (2013)
  • Author(s): Katsuto Takenaka
  • Organizer: the 55th American Society of Hematology Annual Meeting
  • Place of Presentation: New Orleans, LA, USA
• [Presentation] 同種造血幹細胞移植後早期のCMV再活性化が急性白血病再発に及ぼす影響 (2013)
  • Author(s): 竹中克斗
  • Organizer: 第35回日本造血細胞移植学会
  • Place of Presentation: 金沢
• [Presentation] ヒト造血アッセイのための異種移植システムの進歩 (2012)
  • Author(s): 竹中克斗
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-20
  • Invited
• [Presentation] 急性骨髄性白血病幹細胞遺伝子発現プロファイルの臨床的意義 (2012)
  • Author(s): 竹中克斗
  • Organizer: 第22回日本サイトメトリー学会
  • Place of Presentation: 大阪
  • Year and Date: 2012-06-30
  • Invited
• [Presentation] Hemophagocytic lymphohistiocytosis is caused by engulfment of hematopoietic stem cells by macrophages through stem cell-specific suppression of CD47 under influence of cytokine deregulation (2011)
  • Author(s): Kuriyama T, Takenaka K, et al
  • Organizer: 第53回米国血液学会
  • Place of Presentation: サンディエゴ、米国
  • Year and Date: 2011-12-12
• [Presentation] The efficient engraftment of human hematopoiesis in the Balb/c strain is mounted by Balb/c-specific SIRPA polymorphism that enhances binding affinity to human CD47 (2011)
  • Author(s): Iwamoto C, Takenaka K, et al
  • Organizer: 第53回米国血液学会
  • Place of Presentation: サンディエゴ、米国
  • Year and Date: 2011-12-12
• [Presentation] Hemophagocytic Lymphohistiocytosis Is Caused by Engulfment of Hematopoietic Stem Cells by Macrophages Through Stem Cell-Specific Suppression of CD47 Under Influence of Cytokine Deregulation (2011)
  • Author(s): Kuriyama T, Takenaka K, et al
  • Organizer: Annual Meeting of the American Society of Hematology 2011
  • Place of Presentation: San Diego、米国
• [Presentation] The Efficient Engraftment of Human Hematopoiesis in the Balb/c Strain Is Mounted by Balb/c-Specific SIRPA Polymorphism That Enhances Binding Affinity to Human CD47 (2011)
  • Author(s): Iwamoto C, Takenaka K, et al
  • Organizer: Annual Meeting of the American Society of Hematology 2011
  • Place of Presentation: San Diego、米国
• [Presentation] 日本造血細胞移植学会ガイドライン サイトメガロウイルス感染症
  • Author(s): 竹中克斗
  • Organizer: 第34回日本造血細胞移植学会
  • Place of Presentation: 大阪