HOME > Members > GCOE Organizing Members > Tomoki Naoe MD, PhD


Tomoki Naoe MD, PhDProfessor, Department of Hematology and Oncology, Nagoya University Graduate School of Medicine


Specialized field

Hematology / Oncology

Career Summary

1976,
M.D., Nagoya University School of Medicine
1976-1980,
Resident, Internal Medicine, Nagoya 1st Red Cross Hospital
1981-1989,
Clinical Fellow, Nagoya University Hospital
1989-1995,
Assistant Professor/Associate Professor, Nagoya University Branch Hospital
1996-2001,
Associate Professor, Nagoya University Hospital
2001-,
Professor, Nagoya University Graduate School of Medicine

Research Theme

Development of target therapy for hematological malignancies

Research Summary

Specific Aims

In order to develop a breakthrough therapy in cancer, it is needed to clarify the molecular pathogenesis of cancer comparing with non-cancer cells, establish molecular targets from the early developmental stage, and search compounds using high-throughput screening. Further approach to develop new therapy is to explore resistant mechanism to therapy and seek the way to overcome the resistance. Here we describe three projects; the first is the approach to target the residual leukemia which is so called “leukemia stem cells” using PI3K/mTOR dual inhibitor, the second is the development of a new mechanism-based anti-cancer drug which targets STAT3/5 signals, and the third is elucidating the mechanism of CD20-negativity of B-cell lymphoma, in which CD20 is positive in immunohistochemistry and negative in flowcytometry.

Achievement

To target leukemia stem cells of Ph+ leukemia, we performed drug screening of small compounds using leukemia-stroma co-culturing system, we found that inhibitors of PI3K/AKT/mTOR-axis signaling, including rapamycin, were promising candidates. Aberrant activation of mTOR signaling has also been reported to be involved in some systems of leukemia initiating cells. In vitro, combination treatment with IM and rapamycin analogue, everolimus (RAD001), induced substantial cell death in the slow-cycling CD34+ population with p70-S6K dephosphorylation and decreased expression of the anti-apoptotic BCL-2 family protein, MCL-1. In the leukemic NOD/SCID mouse ALL model, in vivo RAD001-treatment showed a decrease of tumor burden including slow-cycling CD34+ cells. However, during the cell death by RAD001-treatment, however, negative feedback-loop effects were detected such as reversely increased phosphorylations of AKT (Ser473) and FOXO1/3a. In vitro, the dual PI3K/mTOR inhibitor, NVP-BEZ235 (BEZ), induced substantial cell death including slow-cycling CD34+ cells at lower doses than those required by RAD001. In biomarker analyses, BEZ-treatment inhibited not only p70-S6K phosphorylation but also phosphorylations of mTOR (Ser2481) itself, 4E-BP1, AKT (Ser473) and FOXO1/3a. At the same time, expression of MCL-1 decreased during the cell death by BEZ-treatment. In T315I-mutated BCR-ABL dependent cell lines such as murine Baf3/p210-T315I and human-derived TCC-Y/T315I, treatment with BEZ induced growth inhibition and cell death. The effects of BEZ on normal stem cells and in mouse Ph+ leukemia models are under investigation. These results suggest that treatment with BEZ might have potential for overcoming the resistance to IM due to quiescent property in Ph+ LSCs or T315I-mutation.

OPB-31121 demonstrated strong growth suppressive effect (IC50 < 10 nM) in cell lines of a wide range of cancer especially hematopoietic malignancies including acute myeloid leukemia (AML) with JAK2 mutation or fms-related tyrosine kinase 3 (FLT3) mutation, chronic myeloid leukemia (CML), and myeloma. It is revealed that STAT3 is constitutively activated by tyrosine kinase signal from oncoprotein or oncogenic autocrine of IL-6 pathway in these cell lines. Of note, OPB-31121 had little growth inhibitory effect on normal hematopoietic cells and hardly affected colony formation of human cord blood cells at 100 nM. We also demonstrated growth suppression or regression of cell lines. Furthermore, OPB-31121 induced significant growth suppression of leukemia cells of BCR-ABL-positive acute lymphoblastic leukemia (ALL), CML-blast crisis (BC), CML-BC with T315I mutation in BCR-ABL, and AML with FLT3/ITD. Treatment with cytarabine induced accumulation of quiescent cells that were thought to be relatively resistant to chemotherapy, whereas OPB-31121 did not cause such accumulation, suggesting its effectiveness on quiescent cells. OPB-31121 holds promise as a therapeutic agent against a wide range of hematopoietic malignancies. This drug is under phase 1 trial.

Ten patients with primary DLBCL had CD79a(+)/L26(+) showed CD20 L26-IHC(+)/B1-FCM(-). Quantitative RT-PCR indicated that CD20 mRNA expression that was significantly lower than that of positive control primary DLBCL cells. Immunoblotting analysis showed that CD20 protein expression was relatively lower than that of positive control cells, and no differences in length could be detected. No genetic mutations in the coding sequence of CD20 gene were detected in all samples examined in DNA sequencing analysis, suggesting that CD20 partial deletion is not the main reason for this phenotype. FCM analyses using fluorescent-labeled rituximab indicated that rituximab could partially recognize FCM CD20-B1(-)/CD19(+) B-cells, suggesting that the binding sensitivity of rituximab is much stronger than that of the B1 antibody. Lymphoma cells showing CD20 L26-IHC(+)/B1-FCM(-) phenotype proliferated in NOD-SCID mice and were partially killed by rituximab on in vitro CDC assay. These data suggest that rituximab is effective even for B-lymphoma cells with low CD20 expression if FCM using rituximab can be made to recognize those cell populations. Lower expression of CD20 mRNA may be one of the critical reasons for the CD20 L26-IHC(+)/B1-FCM(-) phenotype. FCM analysis using rituximab may be helpful to detect cell populations that are sensitive to rituximab treatment. Thus, rituximab therapy may be recommended if we can confirm the existence of cell populations recognized by rituximab on FCM.

Principal Research Achievement

  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. 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)
  37. 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)
  38. 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)
  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. Shimada K, Matsue K, Yamamoto K, Murase T, Ichikawa N, Okamoto M, Niitsu N, Kosugi H, Tsukamoto N, Miwa H, Asaoku H, Kikuchi A, Matsumoto M, Saburi Y, Masaki Y, Yamaguchi M, Nakamura S, Naoe T, Kinoshita T. 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)
  41. 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)
  42. 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)
  43. 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)
  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)

Award

1992 Encouraging prize from Japan Society of Hematology
2004 Research award from Japan Leukaemia Research Fund

PAGE TOP