白血病幹細胞の維持機構の解明と治療標的の同定

• Project Area: Development of Novel Treatment Strategies Targeting Cancer Stem Cells
• Project/Area Number: 23130503
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 黒川 峰夫 東京大学, 医学部附属病院, 教授 (80312320)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2012: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2011: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
• Keywords: NF-kb / Adiponectin / Evi1 / JAK2V617F / 白血病幹細胞 / ニッチ

Outline of Annual Research Achievements

われわれは以前、p53ノックアウト造血細胞にJAK2V617F変異を導入して移植すると白血病を発症することを見い出している。この白血病モデルにおいて、分化マーカー陰性cKit陽性Sca-1陽性の最も幼若な白血病細胞、および赤芽球系分化マーカーCD71陽性の白血病細胞が二次移植によって白血病を再構築できることを見出した。本モデルは骨髄増殖性腫瘍から白血病への進展の機構などを追究する上で有用なツールと考えられる。
われわれは、MLL融合遺伝子白血病モデルを用いて、白血病細胞のなかでも幹細胞に富む分画において、NF-kBシグナルが活性化されていること、このような機構が他の白血病モデルやヒト症例検体でも働いていることを示した。この機構の重要性を、in vivo白血病モデルにおいてボルテゾミブなどを用いたNF-kBシグナルの阻害がAML治療効果を認めることによって証明した。さらに、このシグナルの活性化には、自身が産生するTNFalphaによるポジティブフィードバックが重要であることを明らかにした（投稿中）。
骨髄微小環境との相互作用は造血細胞の機能を規定する重要な因子である。われわれは、骨髄に存在する脂肪細胞の重要な液性因子であるアディポネクチン(Adipo)に注目し、そのノックアウトマウスを用いて造血系への作用を解析した。その結果、Adipoを欠く造血環境では、G-CSFや感染に対する顆粒球増殖応答が減弱すること、Adipo投与によりこの応答性が回復することを明らかにした。
また、われわれは、Evi1高発現白血病では高頻度にC/EBPbetaが高発現していること、C/EBPbetaアイソフォームの一つだけがEvi1との協調により白血病発症を促進させることを報告した(Watanabe-Okochi N, et al. Blood in press)。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] The shortest isoform of C/EBPβ, Liver inhibitory protein (LIP) , collaborates with Evi1 to induce AML in a mouse BMT model (2013)
  • Author(s): Okochi, N., Yoshimi, A., Sato, T., Ikeda, T., Kumano, K., Taoka, K., Sato, Y., Shinohara, A., Tsuruta, A., Masuda, A., Yokota, H., Yatomi, Y., Takahashi, K., Kitaura, J., Kitamura, T. and Kurokawa, M
  • Journal Title: Blood Volume: 121 Issue: 20 Pages: 4142-4155
  • DOI: 10.1182/blood-2011-07-368654
  • NAID: 10031196292
  • Peer Reviewed
• [Journal Article] The role of HLA-matched unrelated transplantation in adult patients with Ph chromosome-negative ALL in first remission. A decision analysis. (2013)
  • Author(s): Kako S
  • Journal Title: Bone Marrow Transplantation Volume: 未定 Issue: 8 Pages: 1077-1083
  • DOI: 10.1038/bmt.2013.4
  • Peer Reviewed
• [Journal Article] Impact of a donor source on adult Philadelphia chromosome-negative acute lymphoblastic leukemia: a retrospective analysis from the Adult Acute Lymphoblastic Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. (2013)
  • Author(s): Nishiwaki S
  • Journal Title: Annals of Oncology Volume: 未定 Issue: 6 Pages: 1594-1602
  • DOI: 10.1093/annonc/mds655
  • Peer Reviewed
• [Journal Article] Clinical evaluation of WT1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes. (2013)
  • Author(s): Ueda Y
  • Journal Title: Leukemia & Lymphoma Volume: 未定 Issue: 7 Pages: 1450-1458
  • DOI: 10.3109/10428194.2012.745074
  • Peer Reviewed
• [Journal Article] Erythroleukemia showing early erythroid and cytogenetic responses to azacitidine therapy (2013)
  • Author(s): Sho Hangai
  • Journal Title: Annals of Hematology Volume: 92 Issue: 5 Pages: 707-709
  • DOI: 10.1007/s00277-012-1603-2
  • Peer Reviewed
• [Journal Article] Early-onset Therapy-related Myelodysplastic Syndrome Originating from Prolonged Myelosuppression after Fludarabine-based Therapy (2012)
  • Author(s): Yamazaki S
  • Journal Title: Internal Medicine Volume: 51 Issue: 24 Pages: 3427-3430
  • DOI: 10.2169/internalmedicine.51.8310
  • NAID: 130003308168
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] Generation of induced pluripotent stem cells from primary chronic myelogenous leukemia (2012)
  • Author(s): Keiki Kumano
  • Journal Title: BLOOD Volume: 119 Issue: 26 Pages: 6234-6242
  • DOI: 10.1182/blood-2011-07-367441
  • Peer Reviewed
• [Journal Article] Evaluation of procalcitonin with liquid-phase binding assay in hematological malignancy. (2012)
  • Author(s): Koya J
  • Journal Title: Clinica Chimica Acta Volume: 413 Issue: 19-20 Pages: 1633-1636
  • DOI: 10.1016/j.cca.2012.05.003
  • Peer Reviewed
• [Journal Article] Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. (2012)
  • Author(s): Pinheiro I
  • Journal Title: Cell Volume: 150 Issue: 5 Pages: 948-960
  • DOI: 10.1016/j.cell.2012.06.048
  • Peer Reviewed
• [Journal Article] Thalidomide maintenance therapy for patients with multiple myeloma: meta-analysis. (2012)
  • Author(s): Kagoya Y
  • Journal Title: Leukemia Research Volume: 36 Issue: 8 Pages: 1016-1021
  • DOI: 10.1016/j.leukres.2012.04.001
  • Peer Reviewed
• [Journal Article] Intensive chemotherapy for elderly patients with acute myelogeneous leukemia: a propensity score analysis by the Japan Hematology and Oncology Clinical Study Group (J-HOCS). (2012)
  • Author(s): Oshima K
  • Journal Title: Annals of Hematology Volume: 91 Issue: 10 Pages: 1533-1539
  • DOI: 10.1007/s00277-012-1487-1
  • Peer Reviewed
• [Journal Article] Multiple phosphorylation sites are important for RUNX1 activity in early hematopoiesis and T-cell differentiation. (2012)
  • Author(s): Yoshimi M, Goyama S, Kawazu M, Nakagawa M, Ichikawa M, Imai Y, Kumano K, Asai T, Mulloy JC, Kraft AS, Takahashi T, Shirafuji N, Kurokawa M.
  • Journal Title: Eur J Immunol. Volume: 42 Issue: 4 Pages: 1044-1050
  • DOI: 10.1002/eji.201040746
  • Peer Reviewed
• [Journal Article] Primary MALT lymphoma of the urinary bladder in the background of interstitial cystitis (2012)
  • Author(s): Morita K, Nakamura F, Nannya Y, Nomiya A, Arai S, Ichikawa M, Homma Y, Kurokawa M.
  • Journal Title: Annals of Hematology in press Volume: 91 Issue: 9 Pages: 1505-1506
  • DOI: 10.1007/s00277-012-1419-0
  • Peer Reviewed
• [Journal Article] Treatment of primary intraocular lymphoma with rituximab, high dose methotrexate, procarbazine, and vincristine chemotherapy, reduced whole-brain radiotherapy, and local ocular therapy (2012)
  • Author(s): Taoka K
  • Journal Title: Br J Haematol Volume: 157 Issue: 2 Pages: 252-254
  • DOI: 10.1111/j.1365-2141.2011.08938.x
  • Peer Reviewed
• [Journal Article] Ecotropic viral integration site 1, stem cell self-renewal and leukemogenesis. (2012)
  • Author(s): Kataoka K
  • Journal Title: Cancer Science Volume: 103 Issue: 8 Pages: 1371-1377
  • DOI: 10.1111/j.1349-7006.2012.02303.x
  • Peer Reviewed
• [Journal Article] Lymphoma with specific affinity to endocrine organs (2011)
  • Author(s): 森田剣
  • Journal Title: Ann Hematol. Volume: Nov 22 Issue: 7 Pages: 1149-1150
  • DOI: 10.1007/s00277-011-1372-3
  • Peer Reviewed
• [Journal Article] Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity (2011)
  • Author(s): Keisuke Kataoka
  • Journal Title: The Journal of Experimental Medicine Volume: 208 Issue: 12 Pages: 2403-2416
  • DOI: 10.1084/jem.20110447
  • Peer Reviewed
• [Journal Article] AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors (2011)
  • Author(s): Masahiro Nakagawa
  • Journal Title: Blood Volume: 118 Issue: 25 Pages: 6626-6637
  • DOI: 10.1182/blood-2010-12-326710
  • Peer Reviewed
• [Journal Article] Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through downregulation of p19ARF (2011)
  • Author(s): 黒川峰夫, 他
  • Journal Title: Blood Volume: 118 Issue: 9 Pages: 2541-2550
  • DOI: 10.1182/blood-2010-10-315440
  • Peer Reviewed
• [Journal Article] Evi-1 is a transcriptional target of MLL oncoproteins in hematopoietic stem cells (2011)
  • Author(s): 黒川峰夫, 他
  • Journal Title: Blood Volume: 117 Issue: 23 Pages: 6304-6314
  • DOI: 10.1182/blood-2009-07-234310
  • Peer Reviewed
• [Journal Article] Cas-L regulates myeloid cell motility and suppresses progression of leukemia induced by p210Bcr/Abl (2011)
  • Author(s): 黒川峰夫, 他
  • Journal Title: Cancer Science Volume: 102 Issue: 12 Pages: 2109-2117
  • DOI: 10.1111/j.1349-7006.2011.02066.x
  • Peer Reviewed
• [Journal Article] Evi1 forms a bridge between the epigenetic machinery and signaling pathways (2011)
  • Author(s): Yoshimi A, et al
  • Journal Title: Oncotarget Volume: 2 Pages: 575-586
  • Peer Reviewed
• [Presentation] iPS細胞を用いた造血器腫瘍研究 (2013)
  • Author(s): 黒川 峰夫
  • Organizer: 第12回日本再生医療学会総会
  • Place of Presentation: パシフィコ横浜
  • Invited
• [Presentation] 血液疾患とiPS細胞 (2012)
  • Author(s): 黒川 峰夫
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Invited
• [Presentation] Regulation of chronic myelogenous leukemia stem cells by leukemiaoncogene Evi1 (2011)
  • Author(s): Tomohiko Sato, et al
  • Organizer: ASH 2011
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2011-12-13
• [Presentation] Regulation of chronic myelogenous leukemia stem cells by leukemiaoncogene Evi1 (2011)
  • Author(s): Tomohiko Sato, et al
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] 白血病の分子病態の解明と治療標的の同定 (2011)
  • Author(s): 黒川峰夫
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] 白血病関連転写因子Evi1による慢性骨髄性白血病幹細胞制御 (2011)
  • Author(s): 佐藤智彦, 他
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-05
• [Presentation] 転写因子による造血幹細胞と白血病制御 (2011)
  • Author(s): 黒川峰夫
  • Organizer: 第32回日本炎症・再生医学会
  • Place of Presentation: 京都(招待講演)
  • Year and Date: 2011-06-03
• [Book] 実験医学増刊、がん幹細胞-ステムネス、ニッチ、標的治療への理解 (2011)
  • Author(s): 熊野恵城、黒川峰夫
  • Publisher: 羊土社