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直江 知樹 Tomoki Naoe名古屋大学大学院医学系血液腫瘍内科学・教授・医学博士


専門分野

血液・腫瘍内科学 (造血器腫瘍における分子標的治療の開発)

略歴

1976年 3月
名古屋大学医学部卒業
1976年 4月
名古屋第一赤十字病院
1983年 7月
名古屋大学医学部附属病院分院内科(非常勤医員)
1989年 8月
名古屋大学医学部附属病院分院内科(助手)
1992年 7月
名古屋大学医学部附属病院分院内科(講師)
1994年 3月
名古屋大学医学部附属病院分院内科(助教授)
1996年12月
名古屋大学医学部附属病院難治感染症部(助教授)
2001年 4月
名古屋大学医学部附属病院難治感染症部(教授)
2002年 4月
名古屋大学大学院医学系研究科(教授)

研究課題名

造血器腫瘍の分子標的治療開発

これまでの成果と今後の展望

A. 研究目的
“がん”における画期的な治療法を開発するためには、“がん”と“正常”組織における違いを分子あるいは細胞生物学的に明らかにし、開発コンセプトから分子あるいは細胞に標的を定め、ハイスループットな薬剤スクリーニングを経て、動物モデルからヒトへのトランスレーションを図る必要がある。我々は血液腫瘍の変異分子あるいは幹細胞に着目し、分子病態の理解を進め、新たな分子診断・分子標的治療法の開発を行い、さらにこれまでに開発された分子標的治療への耐性克服と残存根治を目指した研究を行ってきた。今年度は?ABLキナーゼ阻害剤治療における白血病の幹細胞分画残存と残存の克服、?がん細胞における重要なシグナル分子STAT3/5を標的とした阻害剤の開発、?B細胞リンパ腫におけるCD20低発現の分子メカニズムの解明、について研究を行った。

B. 研究成果
[1] 慢性骨髄性白血病(CML)ではイマチニブ(IM)に著効を示しても微小残存白血病(MRD)が持続しIM中止後は再発することが知られている。今回、IMあるいは第2世代ABLキナーゼ阻害剤を開始した患者合計47名に於いて、一年間あるいは長期投与における白血病幹細胞(CD34+38-分画)ならびに前駆細胞(CD34+38+分画)のBCR-ABL転写物コピー数/BCR転写物コピー数をフォローして、第2世代ABLキナーゼ阻害剤では幹細胞分画も含めてより急峻にこの比率が低下することを確認した。幹細胞分画における静止期細胞が耐性に関わる可能性が示されているが、PI3K・mTORダブル阻害剤BEX235の併用はex vivoにおいて有意にCD34陽性静止期細胞を抑制することを示した(図左)。
[2] STAT3/5は受容体あるいは非受容体チロシンキナーゼの下流に位置し、がん細胞の増殖・生存などに重要で、シグナル分子かつ転写因子として働く。OPB-31121は肝線維化抑制物質として大塚製薬で発見されたが、その後の研究で様々な腫瘍細胞株に増殖抑制効果を示すことが明らかとなり、我々が共同研究を進めている化合物である。この化合物は細胞株やマウスへの移植細胞株において、ナノモルレベルで強力なSTATリン酸化抑制作用を有しているが、JAK2を含めた上流のチロシンキナーゼ阻害剤には一切直接的な抑制効果を認めなかった。またJAK2によるSTAT3のin vitroリン酸化では直接抑制効果を示さないことから、その分子機序を解析中である。患者白血病移植マウスでは白血病を抑制しマウス正常骨髄を回復させた(図右上)。この化合物については前臨床を終了し現在臨床第一相試験が行われている。
[3] B細胞リンパ腫に対する抗CD20抗体リツキシマブ併用化学療法は標準療法となっているが、再発時にはCD20陰転化を認めることがあることを報告してきた(Hiraga J et al. BLOOD 2009)。今回は初診時からCD20免疫染色陽性でありながらフローサイトメトリー陰性であるB細胞リンパ腫の検体を用いて、その分子背景とリツキシマブへの反応性を解析した。フローサイトメトリー陰性の背景には細胞表面への発現低下、CD20遺伝子発現の低下があるが、CD20遺伝子変異は検出されなかった。リツキシマブの補体依存性細胞傷害性はフローサイトメトリー陽性検体に比較し若干の低下が認められた(図右下)。

主要研究業績

  1. Mizuno H, Nakayama T, Miyata Y, Saito S, Nishiwaki S, Nakao N, Takeshita K, Naoe T: Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib. Leukemia, in press (2012)
  2. Minami Y, Abe A, Minami M, Kitamura K, Hiraga J, Mizuno S, Ymamoto K, Sawa M, Inagaki Y, Miyamura K, Naoe T: Retention of CD34(+) CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors. Leukemia, in press (2012)
  3. Ohnishi K, Nakaseko C, Takeuchi J, Fujisawa S, Nagai T, Yamazaki H, Tauchi T, Imai K, Mori N, Yagasaki F, Maeda Y, Usui N, Miyazaki Y, Miyamura K, Kiyoi H, Ohtake S, Naoe T: Long-term outcome of imatinib therapy, with assessment of its dosage and blood levels, for chronic myelogenous leukemia. Cancer Sci, in press (2012)
  4. Iriyama C, Tomita A, Hoshino H, Adachi-Shirahata M, Furukawa-Hibi Y, Yamada K, Kiyoi H, Naoe T: Using peripheral blood circulating DNAs to detect CpG global methylation status and genetic mutations in patients with myelodysplastic syndrome. Biochem Biophys Res Commun, 419, 662-669 (2012)
  5. Tokunaga T, Shimada K, Yamamoto K, Chihara D, Ichihashi T, Oshima R, Tanimoto M, Iwasaki T, Isoda A, Sakai A, Kobayashi H, Kitamura K, Matsue K, Taniwaki M, Tamashima S, Saburi Y, Masunari T, Naoe T, Nakamura S, Kinoshita T: Retrospective analysis of prognostic factors for angioimmunoblastic T-cell lymphoma: a multicenter cooperative study in Japan. Blood, 119, 2837-2843 (2012)
  6. Kajiguchi T, Katsumi A, Tanizaki R, Kiyoi H, Naoe T: Y654 of beta-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of beta-catenin. Eur J Haematol, 88, 314-320 (2012)
  7. Kimura H, Ito Y, Kawabe S, Gotoh K, Takahashi Y, Kojima S, Naoe T, Esaki S, Kikuta A, Sawada A, Kawa K, Ohshima K, Nakamura S: EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. Blood, 119, 673-686 (2012)
  8. Saito S, Nakayama T, Hashimoto N, Miyata Y, Egashira K, Nakao N, Nishiwaki S, Hasegawa M, Hasegawa Y, Naoe T: Mesenchymal stem cells stably transduced with a dominant-negative inhibitor of CCL2 greatly attenuate bleomycin-induced lung damage. Am J Pathol, 179, 1088-1094 (2011)
  9. Goto E, Tomita A, Hayakawa F, Atsumi A, Kiyoi H, Naoe T: Missense mutations in PML-RARA are critical for the lack of responsiveness to arsenic trioxide treatment. Blood, 118, 1600-1609 (2011)
  10. Murase M, Nishida T, Onizuka M, Inamoto Y, Sugimoto K, Imahashi N, Murata M, Miyamura K, Kodera Y, Inoko H, Naoe T: Cytotoxic T-lymphocyte antigen 4 haplotype correlates with relapse and survival after allogeneic hematopoietic SCT. Bone Marrow Transplant, 46, 1444-1449 (2011)
  11. Tomita A, Shirasugi Y, Ito T, Tsurumi H, Naoe T: Extravascular hemolytic attack after eculizumab therapy for paroxysmal nocturnal hemoglobinuria. Ann Hematol, in press (2011)
  12. Ishiyama K, Takami A, Kanda Y, Nakao S, Hidaka M, Maeda T, Naoe T, Taniguchi S, Kawa K, Nagamura T, Tabuchi K, Atsuta Y, Sakamaki H: Prognostic factors for acute myeloid leukemia patients with t(6;9)(p23;q34) who underwent an allogeneic hematopoietic stem cell transplant. Leukemia, in press (2011)
  13. Katsumi A, Nishida T, Murata M, Terakura S, Shimada K, Saito S, Kobayashi M, Kodaira A, Shibata S, Oda I, Yagi T, Kiyoi H, Matsushita T, Kojima T, Naoe T: Virus-associated hemophagocytic syndrome caused by pandemic swine-origin influenza A (H1N1) in a patient after unrelated bone marrow transplantation. J Clin Exp Hematop, 51, 63-65 (2011)
  14. Terakura S, Atsuta Y, Sawa M, Ohashi H, Kato T, Nishiwaki S, Imahashi N, Yasuda T, Murata M, Miyamura K, Suzuki R, Naoe T, Ito T, Morishita Y; for the Nagoya Blood and Marrow Transplantation Group: A prospective dose-finding trial using a modified continual reassessment method for optimization of fludarabine plus melphalan conditioning for marrow transplantation from unrelated donors in patients with hematopoietic malignancies. Ann Oncol, 22, 1865-1871 (2011)
  15. Kurahashi S, Hayakawa F, Miyata Y, Yasuda T, Minami Y, Tsuzuki S, Abe A, Naoe T: PAX5-PML acts as a dual dominant-negative form of both PAX5 and PML. Oncogene, 30, 1822-1830 (2011)
  16. Miyawaki S, Ohtake S, Fujisawa S, Kiyoi H, Shinagawa K, Usui N, Sakura T, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R: A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood, 117, 2366-2372 (2011)
  17. Akao Y, Iio A, Itoh T, Noguchi S, Itoh Y, Ohtsuki Y, Naoe T: Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther, 19, 395-399 (2011)
  18. Kako S, Morita S, Sakamaki H, Ogawa H, Fukuda T, Takahashi S, Kanamori H, Onizuka M, Iwato K, Suzuki R, Atsuta Y, Kyo T, Sakura T, Jinnai I, Takeuchi J, Miyazaki Y, Miyawaki S, Ohnishi K, Naoe T, Kanda Y: A decision analysis of allogeneic hematopoietic stem cell transplantation in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission who have an HLA-matched sibling donor. Leukemia, 25, 259-265 (2011)
  19. Mizuta S, Matsuo K, Yagasaki F, Yujiri T, Hatta Y, Kimura Y, Ueda Y, Kanamori H, Usui N, Akiyama H, Miyazaki Y, Ohtake S, Atsuta Y, Sakamaki H, Kawa K, Morishima Y, Ohnishi K, Naoe T, Ohno R: Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymphoblastic leukemia. Leukemia, 25, 41-47 (2011)
  20. Ono T, Takeshita A, Iwanaga M, Asou N, Naoe T, Ohno R; Japan Adult Leukemia Study Group: Impact of additional chromosomal abnormalities in patients with acute promyelocytic leukemia: 10-year results of the Japan Adult Leukemia Study Group APL97 study. Haematologica, 96, 174-176 (2011)
  21. Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinagawa K, Usui N, Okumura H, Miyamura K, Nakaseko C, Miyazaki Y, Fujieda A, Nagai T, Yamane T, Taniwaki M, Takahashi M, Yagasaki F, Kimura Y, Asou N, Sakamaki H, Handa H, Honda S, Ohnishi K, Naoe T, Ohno R: Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood, 117, 2358-2365 (2011)
  22. Ishikawa Y, Kiyoi H, Watanabe K, Miyamura K, Nakano Y, Kitamura K, Kohno A, Sugiura I, Yokozawa T, Hanamura A, Yamamoto K, Iida H, Emi N, Suzuki R, Ohnishi K, Naoe T: Trough plasma concentration of imatinib reflects BCR-ABL kinase inhibitory activity and clinical response in chronic-phase chronic myeloid leukemia: a report from the BINGO study. Cancer Sci, 101, 2186-2192 (2010)
  23. Nakao N, Nakayama T, Yahata T, Muguruma Y, Saito S, Miyata Y, Yamamoto K, Naoe T: Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells. Am J Pathol, 177, 547-554 (2010)
  24. Shimada K, Murase T, Matsue K, Okamoto M, Ichikawa N, Tsukamoto N, Niitsu N, Miwa H, Asaoku H, Kosugi H, Kikuchi A, Matsumoto M, Saburi Y, Masaki Y, Yamamoto K, Yamaguchi M, Nakamura S, Naoe T, Kinoshita T; IVL Study Group in Japan: Central nervous system involvement in intravascular large B-cell lymphoma: a retrospective analysis of 109 patients. Cancer Sci, 101, 1480-1486 (2010)
  25. Yamashita Y, Yuan J, Suetake I, Suzuki H, Ishikawa Y, Choi YL, Ueno T, Soda M, Hamada T, Haruta H, Takada S, Miyazaki Y, Kiyoi H, Ito E, Naoe T, Tomonaga M, Toyota M, Tajima S, Iwama A, Mano H: Array-based genomic resequencing of human leukemia. Oncogene, 29, 3723-3731 (2010)
  26. Tanizaki R, Nomura Y, Miyata Y, Minami Y, Abe A, Hanamura A, Sawa M, Murata M, Kiyoi H, Matsushita T, Naoe T: Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD/SCID/IL-2Rgammac-/- mice. Cancer Sci, 101, 631-638 (2010)
  27. Miyata Y, Liu Y, Jankovic V, Sashida G, Lee JM, Shieh JH, Naoe T, Moore M, Nimer SD: Cyclin C regulates human hematopoietic stem/progenitor cell quiescence. Stem Cells, 28, 308-317 (2010)
  28. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European LeukemiaNet: Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood, 115, 453-474 (2010)
  29. Miyata Y, Liu Y, Jankovic V, Sashida G, Lee JM, Shieh JH, Naoe T, Moore M, Nimer SD. Cyclin C Regulates Human Hematopoietic Stem/Progenitor Cell Quiescence. Stem Cells, 28 308-317 (2010)
  30. Tanizaki R, Nomura Y, Miyata Y, Minami Y, Abe A, Hanamura A, Sawa M, Murata M, Kiyoi H, Matsushita T, Naoe T. Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD / SCID / IL-2Rgammac mice. Cancer Sci, 101, 631-638 (2009)
  31. Sugimoto K, Murata M, Terakura S, Naoe T. CTL clones isolated from an HLA-Cw-mismatched bone marrow transplant recipient with acute graft-versus-host disease. J Immunol, 183, 5991-5998 (2009)
  32. Shimada K, Kinoshita T, Naoe T, Nakamura S. Presentation and management of intravascular large B-cell lymphoma. Lancet Oncol, 10, 895-902 (2009)
  33. Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, Ishii K, Mori Y, Ozeki K, Minami Y, Abe A, Maeda H, Akiyama T, Kanda Y, Sato Y, Akinaga S, Naoe T. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood, 114, 1607-1617(2009)
  34. Hiraga J, Tomita A, Sugimoto T, Shimada K, Ito M, Nakamura S, Kiyoi H, Kinoshita T, Naoe T. Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance. Blood, 113, 4885-4893 (2009)
  35. Furuhata A, Murakami M, Ito H, Gao S, Yoshida K, Sobue S, Kikuchi R, Iwasaki T, Takagi A, Kojima T, Suzuki M, Abe A, Naoe T, Murate T. GATA-1 and GATA-2 binding to 3' enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines. Leukemia, 23, 1270-1277 (2009)
  36. Minami Y, Stuart SA, Ikawa T, Jiang Y, Banno A, Hunton IC, Young DJ, Naoe T, Murre C, Jamieson CH, Wang JY. BCR-ABL-transformed GMP as myeloid leukemic stem cells. Proc Natl Acad Sci USA, 105, 17967-17972 (2008)
  37. Yanada M, Sugiura I, Takeuchi J, Akiyama H, Maruta A, Ueda Y, Usui N, Yagasaki F, Yujiri T, Takeuchi M, Nishii K, Kimura Y, Miyawaki S, Narimatsu H, Miyazaki Y, Ohtake S, Jinnai I, Matsuo K, Naoe T, Ohno R; Japan Adult Leukemia Study Group. Prospective monitoring of BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy. Br J Haematol, 143, 503-510 (2008)
  38. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, Naoe T, Lengfelder E, Büchner T, Döhner H, Burnett AK, Lo-Coco F. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood, 113, 1875-1891 (2009)
  39. Hayakawa F, Abe A, Kitabayashi I, Pandolfi PP, Naoe T. Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis. J Biol Chem, 283, 24420-24425 (2008)
  40. Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, Nishii K, Ueda Y, Takeuchi M, Miyawaki S, Maruta A, Narimatsu H, Miyazaki Y, Ohtake S, Jinnai I, Matsuo K, Naoe T, Ohno R; Japan Adult Leukemia Study Group. Karyotype at diagnosis is the major prognostic factor predicting relapse-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy. Haematologica, 93, 287-290 (2008)
  41. Xu J, Suzuki M, Niwa Y, Hiraga J, Nagasaka T, Ito M, Nakamura S, Tomita A, Abe A, Kiyoi H, Kinoshita T, Naoe T. Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome. Br J Haematol, 140, 394-401 (2008)
  42. Narimatsu H, Yokozawa T, Iida H, Tsuzuki M, Hayakawa M, Takeo T, Iino M, Ichihashi T, Kato C, Sawamoto A, Sao H, Yanada M, Emi N, Kiyoi H, Yamaguchi T, Naoe T, Suzuki R, Sugiura I. Clinical characteristics and outcomes in patients with t(8;21) acute myeloid leukemia in Japan. Leukemia, 22, 428-432 (2008)
  43. Shimada K et al. Retrospective analysis of intravascular large B-cell lymphoma treated with rituximab-containing chemotherapy as reported by the IVL study group in Japan. J. Clin. Oncol. 26: 3189-3195 (2008)
  44. Kiyoi H et al. A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations. Clin. Cancer Res. 13: 4575-4582 (2007)
  45. Yoshida H et al. PML-retinoic acid receptor alpha inhibits PML IV enhancement of PU.1-induced C/EBPepsilon expression in myeloid differentiation. Mol. Cell Biol. 27: 5819-5834 (2007)
  46. Ninomiya M et al. Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice. Leukemia 21: 136-142 (2007)
  47. Yanada M et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J. Clin. Oncol. 24: 460-466 (2006)
  48. Suzuki T et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood 106: 2854-2861 (2005)
  49. Katsumi A et al. Integrin activation and matrix binding mediate cellular responses to mechanical stretch. J. Biol. Chem. 280: 16546-16549 (2005)
  50. Ozeki K et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 103: 1901-1908 (2004)
  51. Minami Y et al. Different antiapoptotic pathways between wild-type and mutated FLT3: insights into therapeutic targets in leukemia. Blood 102: 2969-2975 (2003)
  52. Akatsuka Y et al. Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens. J. Exp. Med. 197: 1489-500 (2003)
  53. Kiyoi H et al. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene 21: 2555-2263 (2002)
  54. Yamamoto Y et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97: 2434-2439 (2001)
  55. Hayakawa F et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 19: 624-631 (2000)
  56. Naoe T et al. Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy-related leukemia/ myelodysplastic syndrome and de novo acute myeloid leukemia. Clin. Cancer Res. 6: 4091-4095 (2000)

受賞

1992年 日本血液学会奨励賞
2004年 日本白血病研究基金一般研究賞

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