Establishment of a novel therapeutic strategy for leukemia by targeting the hematopoietic stem cell niche.

• Project/Area Number: 24390248
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tokai University
• Principal Investigator: ANDO Kiyoshi 東海大学, 医学部, 教授 (70176014)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2013: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2012: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: 白血病幹細胞 / 白血病ニッチ / PAI-1 / PAI-1阻害剤 / 骨髄形成症候群 / ニッチ

Outline of Final Research Achievements

We have reported that plasminogen activator inhibitor-1 (PAI-1), a negative regulator of the fibrinolytic pathway, expressed in the BM niche and negatively regulated the hematopoietic regeneration in the BM microenvironment. Pharmacological inhibition of PAI-1 activity significantly improved hematopoietic recovery after hematopoietic stem cell transplantation. In this study, we demonstrated several evidences about the relationship leukemia and PAI-1. First, leukemia stem cells highly expressed the PAI-1. Second, PAI-1-expressinng leukemia showed resistance to anti-tumor therapy. Finally, co-administration of leukemia-specific molecular target drug and PAI-1 inhibitor facilitated anti-tumor effects. Our results indicate that the inhibition of PAI-1 activity could be a therapeutic approach to eliminate the therapy-resistant leukemia stem cells.

Research Products

• [Journal Article] Single nucleotide polymorphism of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients received high dose cytarabine therapy. (2015)
  • Author(s): Amaki J, Onizuka M, Ohmachi K, Aoyama Y, Hara R, Ichiki A, Kawai K, Sato A, Miyamoto M, Toyosaki M, Machida S, Kojima M, Kawada H, Ogawa Y, and Ando K.
  • Journal Title: Int J Hematol, Volume: 12 Pages: 133-133
  • Peer Reviewed
• [Journal Article] Establishment of a humanized APL model via the transplantation of PML-RARA-transduced human common myeloid progenitors into immunodeficient mice. (2015)
  • Author(s): Matsushita H, Yahata T, Sheng Y, Nakamura Y, Muguruma Y, Matsuzawa H, Tanaka M, Hayashi H, Damdinsuren A, Onizuka M, Ito M, Miyachi H, Pandolfi PP, and Ando K.
  • Journal Title: PLoS ONE Volume: 23 Pages: 345-345
  • Peer Reviewed
• [Journal Article] Functional analysis of the SEPT9-ABL1 chimeric fusion gene derived from T-prolymphocytic leukemia. (2015)
  • Author(s): Kawai H, Matsushita H, Suzuki R, Sheng Y, Lu J, Matsuzawa H, Yahata T, Kaneko M, Tsukamoto H, Kawada H, Ogawa Y, Ando K.
  • Journal Title: Leukemia Research Volume: 104 Pages: 567-567
  • Peer Reviewed
• [Journal Article] The clinical outcome of Epstein-Barr virus positive diffuse large B-cell lymphoma of the elderly in rituximab era. (2015)
  • Author(s): Sato A, Nakamura N, Kojima M, Ohmachi K, Esteban JC, Kikuti YY, Numata H, Ohgiya D, Tazume K, Amaki J, Moriuchi M, Miyamoto M, Aoyama Y, Kawai H, Ichiki A, Hara R, Kawada H, Ogawa Y, Ando K
  • Journal Title: Cancer Science, Volume: 228 Pages: 6768-6768
  • Peer Reviewed
• [Journal Article] Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration. (2014)
  • Author(s): IbrahimAA,Yahata T,Onizuka M,Dan T,Van Yperscle De Stribou C,Miyata T,Ando K
  • Journal Title: Stem Cells, Volume: 32 Issue: 4 Pages: 946-958
  • DOI: 10.1002/stem.1577
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of plasminogen activator inhibitor type-1 activity enhances rapid and sustainable hematopoietic regeneration. (2014)
  • Author(s): Ibrahim AA, Yahata T, Onizuka M, Dan T, Van Ypersele De Strihou C, Miyata T, Ando K
  • Journal Title: Stem Cells, Volume: 32 Pages: 959-973
  • Peer Reviewed
• [Journal Article] Deferasirox treatment improved hematopoiesis and led to complete remission in a patient with pure red cell aplasia. (2013)
  • Author(s): Kojima M, Machida S, Miyamoto M, Moriuchi M, Ohbayash Y, Ando K.
  • Journal Title: Int J Hematol. Volume: 98 Pages: 719-722
  • Peer Reviewed
• [Journal Article] Phase I study of intravenous low-dose granulocyte-colony stimulating factor in acute and sub-acute ischemic stroke. (2013)
  • Author(s): Moriya Y, Mizuma A, Uesugi T, Ohnuki Y, Nagata E, Takahashi W, Kobayashi H, Kawada H, Ando K, Takagi S, Takizawa S.
  • Journal Title: Journal of Stroke and Cerebrovascular Diseases Volume: 22 Pages: 1088-1097
  • Peer Reviewed
• [Journal Article] A phase I/II study of VMP (bortezomib-melphalan-prednisolone) for previously untreated patients with multiple myeloma in Japan. (2013)
  • Author(s): Ogawa Y, Suzuki K, Sakai A, Iida S, Ogura M, Tobinai KOgawa Y, Suzuki K, Sakai A, Iida S, Ogura M, Tobinai K,, Matsumoto M, Matsue K, Terui Y, Ohashi K, Ishii M, Mukai H, Ando K, Hotta T
  • Journal Title: Cancer Sci Volume: 104 Pages: 912-919
  • Peer Reviewed
• [Journal Article] Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma. (2013)
  • Author(s): Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, Eom HS, Chae YS, Terauchi T, Tateishi U, Tatsumi M, Kim WS, Tobinai K, Suh C, Ogura M.
  • Journal Title: J Clin Oncol. Volume: 31 Pages: 2103-2109
  • Peer Reviewed
• [Journal Article] Stage I findings of a two-stage Phase II study to assess the efficacy, safety and tolerability of barasertib (AZD1152) compared with low dose cytosine arabinoside in elderly patients with acute myeloid leukemia. (2013)
  • Author(s): Kantarjian H, Martinelli G, Jabbour E, QuintAas-Cardama A, Ando K, Bay J-O, Wei A, Grvpper S, Papayannidis C, Owen K, Pike L, Schmitt N, Stockman P, Giagounidis A,
  • Journal Title: Cancer Volume: 119 Pages: 2611-2619
  • Peer Reviewed
• [Journal Article] High concentrations of L-ascorbic acid specifically inhibit the growth of human leukemic cells via downregulation of HIF-1Fa transcription (2013)
  • Author(s): Kawada H, Kaneko M, Sawanobori M, Uno T, Matsuzawa H, Nakamura Y, Matsushita H, Ando K.
  • Journal Title: PLOS ONE Volume: 8:e62717 Pages: 62717-62717
  • Peer Reviewed
• [Journal Article] RUNX1/AML1 mutant collaborates with BMI1 overexpression in the development of human and murine myelodysplastic syndromes. (2013)
  • Author(s): Harada Y, Inoue D, Ding Y, Imagawa J, Doki N, Matsui H, Yahata T, Matsushita H, Ando K, Sashida G, Iwama A, Kitamura T, and Harada H
  • Journal Title: Blood Volume: 121 Pages: 3434-3446
  • Peer Reviewed
• [Journal Article] Scanning of the immunogenome with microsatellite markers for non-HLA associations with graft-versus-host disease in haematopoietic stem cell transplantation. (2013)
  • Author(s): Harkensee C, Oka A, Onizuka M, Middleton PG, Inoko H, Nakaoka H, Gennery AR, Ando K and Morishima Y.
  • Journal Title: Immunogenetics Volume: 65 Pages: 417-427
  • Peer Reviewed
• [Journal Article] MYC rearrangements are useful for predicting outcomes following rituximab and chemotherapy: multi-center analysis of Japanese patients with diffuse large B-cell lymphoma. (2013)
  • Author(s): Kojima M, Nishikii H, Takizawa J, Aoki S, Noguchi M, Chiba S, Ando K, and Nakamura N.
  • Journal Title: Leuk. Lymphoma Volume: 54 Pages: 2149-2154
  • Peer Reviewed
• [Journal Article] Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (2013)
  • Author(s): Ohmachi K., et al
  • Journal Title: J Clin Oncol Volume: (in press)
  • Peer Reviewed
• [Journal Article] MYC rearrangements are useful for predicting ou tcomes following rituxiraab and chemotherapy : multi-center analysis of Japanese patients with diffuse large B-cell lymphoma (2013)
  • Author(s): Kojima M., et al
  • Journal Title: Leuk. Lymphoma Volume: (in press)
  • Peer Reviewed
• [Journal Article] High concentrations of L-ascorbic acid specifically inhibit the growth of human leukemic cells via downregulation of HIF -1Fa transcription (2013)
  • Author(s): Kawada H., et al
  • Journal Title: PLOS ONE Volume: (in press)
  • Peer Reviewed
• [Journal Article] Imatinib mesylate directly impairs class switch recombination through downregulation of AID. (2012)
  • Author(s): Kawamata T, Lu J, Sato T, Tanaka M, Nagaoka H, Agata Y, Toyoshima T, Yokoyama K, Oyaizu N, Nakamura N, Ando K, Tojo A, Kotani A
  • Journal Title: Blood Volume: 119 Issue: 13 Pages: 3123-3127
  • DOI: 10.1182/blood-2011-01-327932
  • Peer Reviewed
• [Journal Article] Phase I Study of Anti -CD22 Immunoconjugate Inotuzumab Ozogamicin Plus Rituximab in Relapsed/Refractory B-cell Non-Hodgkin Lymphoma (2012)
  • Author(s): Ogura M., et al
  • Journal Title: Cancer Science Volume: 103 Pages: 933-938
  • Peer Reviewed
• [Journal Article] Clinical and pathological features of B-cell non-Hodgkin lyraphomas lacking surface expression of immunoglobulin light chains (2012)
  • Author(s): Matsushita H., et al
  • Journal Title: Clinical Chemistry and Laboratory Medicine Volume: 50 Issue: 9 Pages: 1665-1670
  • DOI: 10.1515/cclm-2011-1854
  • Peer Reviewed
• [Journal Article] PML affects IL-6 production and resistance to treatment in multiple myeloma (2012)
  • Author(s): Ohgiya D., et al
  • Journal Title: Acta Haematologica Volume: 128 Issue: 4 Pages: 213-222
  • DOI: 10.1159/000339486
  • Peer Reviewed
• [Journal Article] Huge multinucleated megaloblasts found in a patient with refractory anemia with excess blasts-1 (2012)
  • Author(s): Ohgiya D., et al
  • Journal Title: Int J Hematol Volume: 96 Issue: 5 Pages: 631-632
  • DOI: 10.1007/s12185-012-1212-9
  • Peer Reviewed
• [Journal Article] Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc. (2012)
  • Author(s): Sakai, D. et al.
  • Journal Title: Nature Comm. Volume: 3 Issue: 1 Pages: 1264-1264
  • DOI: 10.1038/ncomms2226
  • Peer Reviewed
• [Presentation] A rare genetic polymorphism in C5 confers poor response to the anti-C5 monoclonal antibody eculizuroab by nine Japanease patients with PNH (2012)
  • Author(s): 西村 純一
  • Organizer: アメリカ血液学会(ASH)
  • Place of Presentation: アメリカ(アトランタ)
  • Year and Date: 2012-12-10
• [Presentation] Risk factor for early phase cytomegaloviremia after allo-HSCT (2012)
  • Author(s): 青山 泰之
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-10-21
• [Presentation] Functional analysis of SEPT9-ABL1 chimeric fusion gene derived from T-prolymphocytic leukemia (2012)
  • Author(s): 松下 弘道
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-10-21
• [Presentation] 急性リンパ性白血病に対する同種造血幹細胞移植後死亡の臨床的特徴 (2012)
  • Author(s): 町田真一郎
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-10-20
• [Presentation] Autologous SCT and allogeneic reduced intensity SCT as curative treatment for PTCL-NOS (2012)
  • Author(s): 扇屋 大輔
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-10-19
• [Presentation] Effect determine of treatment to acute myeloid leukemia by chemotherapy or Hematopoietic stem cell transplantation (2012)
  • Author(s): 川井 英嗣
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-10-19
• [Presentation] Non-telomeric stem cell aging in hematopoietic regeneration (2012)
  • Author(s): 八幡 崇
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-10-19
• [Presentation] 骨髄異形成症候群(MDS)と慢性骨髄単球性白血病(CMML)に対するアザシチジン(AZA)の有効性 (2012)
  • Author(s): 村山 弘道
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-10-19
• [Presentation] Ara-C代謝に関連する遺伝子多型とHDACを行ったAML患者の治療成績の検討 (2012)
  • Author(s): 天木 惇
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2012-10-19
• [Presentation] 未治療骨髄腫に対するVMP療法:国内第I/II相臨床試験成績 (2012)
  • Author(s): 飯田 信介
  • Organizer: 第35回日本高血圧学会
  • Place of Presentation: ウェスティンナゴヤキャッスル(名古屋)
  • Year and Date: 2012-09-20
• [Presentation] Stage I findings of a two-stage Phase II study to assess the efficacy, safety and tolerability of barasertib (AZD1152) compared with low dose cytosine arabinoside (LDAC) in elderly patients (pts)with acute myeloid leukemia (AML) (2012)
  • Author(s): Hagop Kantarjian
  • Organizer: 第48回アメリカ癌治療学会(ASCO)
  • Place of Presentation: アメリカ(シカゴ)
  • Year and Date: 2012-06-15
• [Presentation] A multicenter phase 2 study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) or mantle cell lymphoma (MCL) (2012)
  • Author(s): Kiyoshi Ando
  • Organizer: 第48回アメリカ癌治療学会(ASCO)
  • Place of Presentation: アメリカ(シカゴ)
  • Year and Date: 2012-06-15
• [Patent(Industrial Property Rights)] PAI-1阻害剤の新規用途 (2014)
  • Inventor(s): 安藤潔、八幡崇、宮田敏男
  • Industrial Property Rights Holder: 安藤潔、八幡崇、宮田敏男
  • Industrial Property Rights Type: 特許
  • Filing Date: 2014-04-15
  • Overseas