Establishment of a platform for elucidation of molecular pathogenesis of leukemia and antileukemia therapy based on integrated pathway analysis

• Project/Area Number: 24249055
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: KUROKAWA MINEO 東京大学, 医学部附属病院, 教授 (80312320)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥44,850,000 (Direct Cost: ¥34,500,000、Indirect Cost: ¥10,350,000); Fiscal Year 2014: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2013: ¥14,170,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥3,270,000); Fiscal Year 2012: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
• Keywords: Refractory leukemia / Signaling pathway / EVI-1 / BAALC / DNMT3A / NF-kB / JAK2V617F / Lcn2 / Evi1 / オートファジー / 白血病 / Adiponectin / ASXL1

Outline of Final Research Achievements

In this study, we elucidated the down-stream pathway and specific therapeutic target of molecules associated with poor prognosis in acute myeloid leukemia, such as Evi-1 and BAALC, as well as a collaborative factor for Evi-1 induced leukemogenesis and a maintenance mechanism of resistant leukemia initiating cells. By using Evi-1-IRES-GFP knock-in mice, we also showed that Evi-1 marks leukemia initiating cells and Evi-1 is associated with chemoresistance in chronic myeloid leukemia. In addition, we revealed pathogenesis of myeloid malignancies in an integrated manner by demonstrating a mechanisms of leukemia progression, interaction between leukemia cells and surrounding cells and an essential role epigenetic abnormalities play in leukemogenesis. These results provide a foundation to develop novel molecular targeted therapies for refractory hematological malignancies.

Research Products

• [Journal Article] Thrombopoietin/MPL signaling confers growth and survival capacity to CD41-positive cells in a mouse model of Evi1 leukemia. (2014)
  • Author(s): Nishikawa S, Arai S, Masamoto Y, Kagoya Y, Toya T, Watanabe-Okochi N, Kurokawa M.
  • Journal Title: Blood Volume: 124 Issue: 24 Pages: 3587-3596
  • DOI: 10.1182/blood-2013-12-546275
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] JAK2V617F+ myeloproliferative neoplasm clones evoke paracrine DNA damage to adjacent normal cells through secretion of lipocalin-2. (2014)
  • Author(s): Kagoya Y, Yoshimi A, Tsuruta-Kishino T, Arai S, Satoh T, Akira S, Kurokawa M.
  • Journal Title: Blood Volume: 124 Issue: 19 Pages: 2996-3006
  • DOI: 10.1182/blood-2014-04-570572
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia. (2014)
  • Author(s): Sato T, Goyama S, Kataoka K, Nasu R, Tsuruta-Kishino T, Kagoya Y, Nukina A, Kumagai K, Kubota N, Nakagawa M, Arai S, Yoshimi A, Honda H, Kadowaki T, Kurokawa M.
  • Journal Title: Oncogene Volume: 33 Issue: 42 Pages: 5028-5038
  • DOI: 10.1038/onc.2014.108
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. (2014)
  • Author(s): Kagoya Y, Yoshimi A, Kataoka K, Nakagawa M, Kumano K, Arai S, Kobayashi H, Saito T, Iwakura Y, Kurokawa M.
  • Journal Title: J Clin Invest. Volume: 124 Issue: 2 Pages: 528-542
  • DOI: 10.1172/jci68101
  • Peer Reviewed
• [Journal Article] Distribution of serum erythropoietin levels in lower risk myelodysplastic syndrome cases with anemia. (2014)
  • Author(s): Nakazaki K, Nannya Y, and Kurokawa M.
  • Journal Title: Int J Hematol Volume: 99(1) Issue: 1 Pages: 53-56
  • DOI: 10.1007/s12185-013-1485-7
  • Peer Reviewed
• [Journal Article] Serial Profile of Vitamins and Trace Elements during the Acute Phase of Allogeneic Stem Cell Transplantation. (2013)
  • Author(s): Nannya Y, Shinohara A, Ichikawa M, and Kurokawa M.
  • Journal Title: Biol Blood Marrow Transplant Volume: In Press
  • Peer Reviewed
• [Journal Article] Single-cell gene expression analysis reveals clonal architecture of blast-phase chronic myeloid leukaemia. (2013)
  • Author(s): Nukina A, Kagoya Y, Watanabe-Okochi N, Arai S, Ueda K, Yoshimi A, Nannya Y, and Kurokawa M.
  • Journal Title: Br J Haematol Volume: In Press Issue: 3 Pages: 580-91
  • DOI: 10.1111/bjh.12726
  • Peer Reviewed
• [Journal Article] A mixed-type autoimmune hemolytic anemia with immune thrombocytopenia related with myositis and post-transplantation lymphoproliferative disorder. (2013)
  • Author(s): Ogura M, Ichikawa M, Masuda A, Kandabashi K, Nannya Y, and Kurokawa M.
  • Journal Title: Ann Hematol. Volume: In Press Issue: 5 Pages: 869-871
  • DOI: 10.1007/s00277-013-1887-x
  • Peer Reviewed
• [Journal Article] Intracellular reactive oxygen species mark and influence the megakaryocyte-erythrocyte progenitor fate of common myeloid progenitors. (2013)
  • Author(s): Shinohara A, Imai Y, Nakagawa M, Takahashi T, Ichikawa M, and Kurokawa M.
  • Journal Title: Stem Cells Volume: 32 Issue: 2 Pages: 548-557
  • DOI: 10.1002/stem.1588
  • Peer Reviewed
• [Journal Article] Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. (2013)
  • Author(s): Goyama S, Schibler J, Cunningham L, Zhang Y, Rao Y, Nishimoto N, Nakagawa M, Olsson A, Wunderlich M, Link KA, Mizukawa B, Grimes HL, Kurokawa M, Liu PP, Huang G, and Mulloy JC.
  • Journal Title: J Clin Invest Volume: 123 Issue: 9 Pages: 3876-3888
  • DOI: 10.1172/jci68557
  • Peer Reviewed
• [Journal Article] A role for RUNX1 in hematopoiesis and myeloid leukemia. (2013)
  • Author(s): Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto N, Watanabe-Okochi N, and Kurokawa M.
  • Journal Title: Int J Hematol Volume: 97 Issue: 6 Pages: 726-734
  • DOI: 10.1007/s12185-013-1347-3
  • NAID: 10031183728
  • Peer Reviewed
• [Journal Article] Acute myeloid leukemia with cryptic CBFB-MYH11 type D. (2013)
  • Author(s): Kobayashi T, Ichikawa M, Kamikubo Y, and Kurokawa M.
  • Journal Title: Int J Clin Exp Pathol. Volume: 6 Pages: 110-112
  • Peer Reviewed
• [Journal Article] The effect of decreased-dose idarubicin for elderly patients with acute myeloid leukemia. (2013)
  • Author(s): Kobayashi T, Ichikawa M, Nannya Y, and Kurokawa M.
  • Journal Title: Jpn J Clin Oncol Volume: 43 Issue: 10 Pages: 1047-1051
  • DOI: 10.1093/jjco/hyt111
  • Peer Reviewed
• [Journal Article] Generation of iPS cells from normal and malignant hematopoietic cells. (2013)
  • Author(s): Kumano K, Arai S, Kurokawa M.
  • Journal Title: Int J Hematol. Volume: 98 Issue: 2 Pages: 145-182
  • DOI: 10.1007/s12185-013-1385-x
  • NAID: 10031194728
  • Peer Reviewed
• [Journal Article] Moxifloxacin is more effective than tosufloxacin in reducing chemotherapy-induced febrile neutropneia in patients with hematological malignancies. (2013)
  • Author(s): Shinohara A, Yoshiki Y, Masamoto Y, Hangaishi A, Nannya Y, and Kurokawa M.
  • Journal Title: Leuk Lymphoma Volume: 54 Issue: 4 Pages: 794-798
  • DOI: 10.3109/10428194.2012.725848
  • Peer Reviewed
• [Journal Article] Simultaneous increase in 1,3-β-D-glucan and procalcitonin levels in Pseudomonas aeruginosa infection. (2013)
  • Author(s): Koya J, Nannya Y, Kobayashi H, Okugawa S, Moriya K, Kurokawa M.
  • Journal Title: J Infect Volume: 67 Issue: 2 Pages: 164-166
  • DOI: 10.1016/j.jinf.2013.03.017
  • Peer Reviewed
• [Journal Article] Simple but powerful prognostic scoring model for MALT lymphoma: a retrospective study. (2013)
  • Author(s): Morita K, Nannya Y, Yoshizato T, Kurokawa M.
  • Journal Title: Ann Hematol Volume: 92 Issue: 3 Pages: 421-423
  • DOI: 10.1007/s00277-012-1585-0
  • Peer Reviewed
• [Journal Article] Unique association of Waldenström macroglobulinemia with optic neuritis and monoclonal T cell expansion. (2013)
  • Author(s): Morita K, Yoshimi A, Masuda A, Ichikawa M, Yatomi Y, Kurokawa M.
  • Journal Title: Int J Hematol Volume: 98 Issue: 2 Pages: 247-249
  • DOI: 10.1007/s12185-013-1372-2
  • Peer Reviewed
• [Journal Article] A case of Schizophyllum commune sinusitis following unrelated cord blood transplantation for acute lymphoblastic leukemia. (2013)
  • Author(s): Toya T, Shinohara A, Tatsuno K, Seo S, Nannya Y, Ichikawa M, Makirnura K Moriya K, Kurokawa M
  • Journal Title: lnternational Journal of Hematology Volume: 98 Issue: 2 Pages: 261-263
  • DOI: 10.1007/s12185-013-1362-4
  • Peer Reviewed
• [Journal Article] Successful treatment with recombinant thrombomodulin for B-cell lymphoma-associated hemophagocytic syndrome complicated by disseminated intravascular coagulation. (2013)
  • Author(s): Uni M, Yoshimi A, Maki H, Maeda D, Nakazaki K, Nakamura F, Fukayama M, Kurokawa M.
  • Journal Title: Int J Clin Exp Pathol Volume: 6 Pages: 1190-1194
  • NAID: 120007089059
• [Journal Article] Transformation of follicular lymphoma in the retroperitoneal muscles demonstrated by CT-guided needle biopsy of FDG-avid lesions; case series. (2013)
  • Author(s): Uni M, Nakamura F, Yoshimi A, Shinozaki-Ushiku A, Hosoi A, Nakazaki K, Nannya Y, Fukayama M, Kurokawa M.
  • Journal Title: Int J Clin Exp Pathol Volume: 7 Pages: 402-406
• [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
• [Presentation] Enhanced autophagy promotes survival of peripheral blast cells from murine acute myeloid leukemia (2014)
  • Author(s): Sumitomo Y, Koya J, Kataoka K, Tsuruta-Kishino T, Morita K, Sato T, Kurokawa M.
  • Organizer: The 56th ASH Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] BAALC promotes leukemogenesis by MAPK-dependent proliferation and KLF4-derived differentiation block (2014)
  • Author(s): Morita K, Masamoto Y, Kagoya Y, Kataoka K, Koya J, Yashiroda H, Sato T, Murata S, Kurokawa M
  • Organizer: The 76th Annual Meeting of the Japanise Society of Hematology
  • Place of Presentation: Osaka
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] The Genetic Landscape Of FPD/AML Revealed CDC25C Mutation As a Driver That Promotes Malignant Transformation (2013)
  • Author(s): Akihide Yoshimi, Takashi Toya, Masahiro Nakagawa, Masahito Kawazu, Yasuhito Nannya, Motoshi Ichikawa, Shunya Arai, Hironori Harada, Kensuke Usuki, Yasuhide Hayashi, Etsuro Ito, Keita Kirito, Hideaki Nakajima, Hiroyuki Mano, and Mineo Kurokawa.
  • Organizer: 55th ASH Annual Meetingand Exposition
  • Place of Presentation: New Orleans
• [Presentation] Modeling Chronic Myelomonocytic Leukemia Through Patient-Derived Induced Pluripotent Stem Cells (2013)
  • Author(s): Keisuke Kataoka, Kazuki Taoka, Masashi Miyauchi, Masataka Hosoi, Keiki Kumano, Shunya Arai, Kazuhiro Toyama, Genta Nagae, Wei Qu, Shinichi Morishita, Hiroyuki Aburatani, and Mineo Kurokawa.
  • Organizer: 55th ASH Annual Meetingand Exposition
  • Place of Presentation: New Orleans
• [Presentation] Disease-Specific Induced Pluripotent Stem Cells Recapitulate The Pathophysiology Of Familial Platelet Disorder With Predisposition To Acute Myelogenous Leukemia (2013)
  • Author(s): Shunya Arai, Hiromitsu Iiduka, Naoya Takayama, Miyauchi Masashi, Kazuki Taoka, Keisuke Kataoka, Masataka Hosoi, Keiki Kumano, Koji Eto, and Mineo Kurokawa.
  • Organizer: 55th ASH Annual Meetingand Exposition
  • Place of Presentation: New Orleans
• [Presentation] Anti-Obese Hormone Adiponectin Regulates Emergency Hematopoiesis and Antibacterial Response Through Downregulation Of Socs3 In Hematopoietic Progenitor Cells (2013)
  • Author(s): Yosuke Masamoto, Shunya Arai, Tomohiko Sato, Akihide Yoshimi, Iseki Takamoto, Naoto Kubota, Takashi Kadowaki, and Mineo Kurokawa.
  • Organizer: 55th ASH Annual Meetingand Exposition
  • Place of Presentation: New Orleans
• [Presentation] Leukemia-Associated Mutations Of DNMT3A Inhibit Differentiation Of Hematopoietic Stem Cells and Promote Leukemic Transformation Through Abberant Recruitment Of Bmi1 (2013)
  • Author(s): Junji Koya, Keisuke Kataoka, Takako Tsuruta-Kishino, Hiroshi Kobayashi, Kensuke Narukawa, Tomohiko Sato, and Mineo Kurokawa.
  • Organizer: 55th ASH Annual Meetingand Exposition
  • Place of Presentation: New Orleans
• [Presentation] Loss Of p53 Induces Leukemic Transformation In a Murine Model Of JAK2V617F-Induced Polycythemia Vera (2013)
  • Author(s): Takako Tsuruta-Kishino, Keisuke Kataoka, Hiroshi Kobayashi, Junji Koya, Kensuke Narukawa, Tomohiko Sato, and Mineo Kurokawa.
  • Organizer: 55th ASH Annual Meetingand Exposition
  • Place of Presentation: New Orleans
• [Presentation] JAK2V617F Mutation Evokes Paracrine DNA Damage To Adjacent Normal Cells Via Secretion Of Lipocalin-2 (2013)
  • Author(s): Yuki Kagoya, Shunya Arai, Akihide Yoshimi, Takako Tsuruta-Kishino, Keisuke Kataoka, and Mineo Kurokawa.
  • Organizer: 55th ASH Annual Meetingand Exposition
  • Place of Presentation: New Orleans
• [Presentation] BAALC Acts As a Scaffold-Like Protein In The ERK Signaling Pathway and Promotes Leukemogenesis By Facilitating MEK–mediated ERK Activation (2013)
  • Author(s): Ken Morita, Keisuke Kataoka, Junji Koya, Takako Tsuruta, Tomohiko Sato, and Mineo Kurokawa.
  • Organizer: 55th ASH Annual Meetingand Exposition
  • Place of Presentation: New Orleans
• [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