Molecular mechanism of enhanced BMI-1 expression in myelodysplastic syndrome with AML1 point mutation.

• Project/Area Number: 20591127
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Hiroshima University
• Principal Investigator: KIMURA Akiro Hiroshima University, 原爆放射線医科学研究所, 教授 (70127645)
• Co-Investigator(Kenkyū-buntansha): MIHARA Keichiro 広島大学, 原爆放射線医科学研究所, 助教 (90363077)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2008: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: AML1 / BMI-1 / 骨髄異形成症候群 / 急性骨髄性白血病 / 慢性骨髄性白血病 / MDS

Research Abstract

BMI-1 plays an important role in selfrenewal of hematopoietic stem cells as well as leukemic stem cells. We investigated the expression in CD34^+ cells from chronic myeloid leukemia (CML). BMI-1 expression was significantly higher in chronic phase compared to controls, and was further increased during the course of the disease progression, accelerated phase and blastic phase. These results suggest the usefullness of BMI-1 expression in CD34^+ cells as a molecular marker for monitoring CML patients in addition to as a therapeutic molecular target. In Lymphoma, high BMI-1 expression was found resistant to both etoposide and oxaliplatin through enhanced expression of survivin.

Research Products

• [Journal Article] Roles of Src-like adaptor protein 2 (SLAP-2) in GPVI-mediated platelet activation SLAP-2 and GPVI signaling. (2010)
  • Author(s): Sugihara, S., Katsutani, S., Deckmyn, H., Fujimura, K., Kimura A
  • Journal Title: Thrombosis Research 126
  • Peer Reviewed
• [Journal Article] Expansion of CD^<8+>/perforin^+ effector memory T cells in the bone marrow of patients with thymoma-associated pure red cell aplasia. (2010)
  • Author(s): Nitta, H., Mihara, K., Sakai, A., Kimura A.
  • Journal Title: British Journal of Haematology 150(6) Pages: 712-715
  • Peer Reviewed
• [Journal Article] Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia. (2010)
  • Author(s): Imagawa, J., Harada, Y., Shimomura, T., Tanaka, H., Okikawa, Y., Hyodo, H., Kimura A., Harada, H.
  • Journal Title: Blood 116(26) Pages: 6018-6022
  • Peer Reviewed
• [Journal Article] 1.治療関連骨髄異形成症候群(MDS)/白血病の疾患概念と疫学.特集・治療関連骨髄異形成症候群(MDS)/白血病 (2010)
  • Author(s): 木村昭郎
  • Journal Title: 血液フロンティア(医薬ジャーナル社) 20(6) Pages: 21-29
• [Journal Article] Roles of Src-like adaptor protein 2 (SLAP-2) in GPVI-mediated platelet activation SLAP-2 and GPVI signaling. (2010)
  • Author(s): Sugihara, S., et al
  • Journal Title: Thrombosis Research Volume: 126
  • Peer Reviewed
• [Journal Article] Giant granulocytic sarcoma of the vagina concurrent with acute myeloid leukemia with t(9;21)(q22;q22) translocation. (2010)
  • Author(s): Imagawa, J., et al
  • Journal Title: International Journal of Hematology Volume: 92 Pages: 553-555
  • Peer Reviewed
• [Journal Article] Expansion of CD8^+/perforin^+ effector memory T cells in the bone marrow of patients with thymoma-associated pure red cell aplasia. (2010)
  • Author(s): Nitta, H., et al
  • Journal Title: British Journal of Haematology Volume: 150 Pages: 712-715
  • Peer Reviewed
• [Journal Article] Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia. (2010)
  • Author(s): Imagawa, J., et al
  • Journal Title: Blood Volume: 116 Pages: 6018-6022
  • Peer Reviewed
• [Journal Article] 1.治療関連骨髄異形成症候群(MDS)/白血病の疾患概念の疫学.特集・治療関連骨髄異形成症候群(MDS)/白血病 (2010)
  • Author(s): 木村昭郎
  • Journal Title: 血液フロンティア Volume: 20 Pages: 21-29
  • Peer Reviewed
• [Journal Article] AML1/RUNX1 point mutation possibly promotes leukemic transformation in myeloproliferative neoplasms. (2009)
  • Author(s): Ding Y, Harada Y, Imagawa J, Kimura A, Harada H
  • Journal Title: Blood 114(25) Pages: 5201-5205
  • Peer Reviewed
• [Journal Article] BMI-1 expression is enhanced through transcriptional and posttranscriptional regulation during the progression of chronic myeloid leukemia. (2009)
  • Author(s): Bhattacharyya, J., Mihara, K., Yasunaga, S., Tanaka, H., Hoshi, M., Takihara, Y., Kimura A
  • Journal Title: Annals of Hematology 88(4) Pages: 333-340
  • Peer Reviewed
• [Journal Article] Activated T-cell-mediated immunotherapy with a chimeric receptor against CD38 in B-cell non-Hodgkin lymphoma. (2009)
  • Author(s): Mihara K, Yanagihara K, Takigahira M, Imai C, Kitanaka A, Takihara Y, Kimura A
  • Journal Title: Journal of Immunotherapy 32(7) Pages: 737-743
  • Peer Reviewed
• [Journal Article] AML1/RUNX1 point mutation possibly promotes leukemic transfor mation in myeloproliferative neoplasms. (2009)
  • Author(s): Ding Y, et al
  • Journal Title: Blood 114 Pages: 5201-5205
  • Peer Reviewed
• [Journal Article] Lenalidomide is active in Japanese patients with symptomatic anemia in low- or intermediate-1 risk myelodysplastic syndromes with a deletion 5q abnormality. (2009)
  • Author(s): Harada H, et al
  • Journal Title: International Journal of Hematology 90 Pages: 353-360
  • Peer Reviewed
• [Journal Article] BMI-1 expression is enhanced through transcriptional and posttrans criptional regulation during the progression of chronic myeloid leukemia. (2009)
  • Author(s): Bhattacharyya J, et al
  • Journal Title: Ann Hematol 88 Pages: 333-340
  • Peer Reviewed
• [Journal Article] Activated T-cell-mediated immunotherapy with a chimeric receptor against CD38 in B-cell non-Hodgkin lymphoma. (2009)
  • Author(s): Mihara K, et al
  • Journal Title: J Immunother. 32 Pages: 737-743
  • Peer Reviewed
• [Journal Article] Acquired pure red cell aplasia associated with malignant lymphomas : a nationwide cohort study in Japan for the PRCA Collaborative Study Group. (2009)
  • Author(s): Hirokawa M, et al
  • Journal Title: Am J Hematol. 84 Pages: 144-148
  • Peer Reviewed
• [Journal Article] High Frequency of AML1/RUNX1 point mutations in radiation-associated myelodysplastic syndrome around Semiplalatinsk nuclear test site. (2008)
  • Author(s): Zharlyganova, D., Harada, H., Harada, Y., Shinkarev, S., Zhumadilov, Z., Zhunusova, A., Tchaizhunusova, N.J., Apsalikov, K., Kemaikin, V., Zhumadilov, K., Kawano, N., Kimura A., Hoshi, M.
  • Journal Title: J.Radiat.Res. 49(5) Pages: 549-555
  • Peer Reviewed
• [Journal Article] on behalf of the Japanese Cooperative Study Group for Intractable Bone Marrow Diseases : Myelodysplastic syndrome with chromosome 5 abnormalities : a nationwide survey in Japan. (2008)
  • Author(s): Tasaka, T., Tohyama, K., Kishimoto, M., Ohyashiki, K., Mitani, K., Hotta, T., Kanamaru, A., Okamoto, S., Karasawa, M., Kimura, A., Tomonaga, M., Uchiyama, T., Ozawa, K.
  • Journal Title: Leukemia 22(10) Pages: 1874-1881
  • Peer Reviewed
• [Journal Article] Ectopic cyclin D1 overexpression increases chemosensitivity but not cell proliferation in multiple myeloma. (2008)
  • Author(s): Kuroda, Y., Sakai, A., Tsuyama, N., Katayama, Y., Munemasa, S., Asaoku, H., Okikawa, Y., Nakaju, N., Mizuno, M., Ogawa, K., Nishisaka, T., Matsui, H., Tanaka, H., Kimura A.
  • Journal Title: International Journal of Oncology 33 Pages: 1201-1213
  • Peer Reviewed
• [Journal Article] High Frequency of AML1/RUNX1 point mutations in radiation-associated myelodysplastic syndrome around Semiplatinsk nuclear test site. (2008)
  • Author(s): Zharlyganova, D.
  • Journal Title: J. Radiat. Res. 49 Pages: 549-555
  • Peer Reviewed
• [Journal Article] Myelodysplastic syndrome with chromosome 5 abnormalities : a nationwide survey in Japan. (2008)
  • Author(s): Tasaka, T.
  • Journal Title: Leukemia 22 Pages: 1874-1881
  • Peer Reviewed
• [Journal Article] Ectopic cyclin D1 overexpression increases chemosensitivity but not cell proliferation in multiple myeloma. (2008)
  • Author(s): Kuroda, Y.
  • Journal Title: International Journal of Oncology 33 Pages: 1201-1213
  • Peer Reviewed
• [Presentation] B-Cell Lymphoma Cells Overexpressing BMI-1 Are Correlated with Drug Resistance through Enhanced Expression of Survivin and Are Effectively Eliminated by T Cells with Anti-CD38 Chimeric Receptor. (2010)
  • Author(s): Bhattacharyya, J., Mihara, K., Ohtsubo, M., Yasunaga, S., Takihara, Y., Hoshi, M., Kimura A.
  • Organizer: 52nd Annual Meeting of the American Society of Hematology
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2010-12-05
• [Presentation] B-cell lymphoma cells overexpressing BMI-1 are correlated with drug resistance through enhanced expression of survivin and are effectively eliminated by T cells with anti-CD38 chimeric receptor. (2010)
  • Author(s): Bhattacharyya, J., et al
  • Organizer: 52^<th> Annual Meeting of the American Society of Hematology
  • Place of Presentation: アメリカ
  • Year and Date: 2010-12-05
• [Presentation] Expansion of CD8^+/perforin^+ effector memory T cells in the bone marrow with thymoma-associated PRCA. (2010)
  • Author(s): Nitta, H., Mihara, K., Sakai, A., Kimura A.
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] Molecular mechanisms to produce MDS/AML by C-terminal trancated type of AML1/RUNX1 mutations. (2010)
  • Author(s): 原田浩徳, 原田結花, 今川潤, 木村昭郎
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] BMI-1 is correlated with drug resistance in B-cell lymphomas through enhanced expression of survivin. (2010)
  • Author(s): Bhattacharyya, J., Mihara, K., Ohtsubo, M., Yasunaga, S., Takihara, Y., Kimura A., Hoshi, M.
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] Expansion of CD8^+/perforin^+ effector memory T cells in the bone macrow with thymoma-associated PRCA. (2010)
  • Author(s): Nitta, H., et al
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] 骨髄増殖性腫瘍からの白血病移行メカニズムの解明 (2010)
  • Author(s): 丁曄、原田結花、今川潤、木村昭郎、原田浩徳
  • Organizer: 第107回日本内科学会講演会
  • Place of Presentation: 東京
  • Year and Date: 2010-04-10
• [Presentation] AML1/RUNX1 Point Mutation Possibly Promotes Leukemic Transformation in Myeloproliferative Disorders. (2009)
  • Author(s): 今川潤, 原田浩徳, 丁曄, 木村昭郎, 原田浩徳
  • Organizer: 51^<th> Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2009-12-05
• [Presentation] Levels of sIL-2R in Sera Depend On Number of CD25-Positive Lymphoma Cells and MMP-9-Positive Macrophages in DLBCL. (2009)
  • Author(s): Yoshida, N., Sakai, A., Okikawa, Y., Katayama, Y., Asaoku, H., Matsui, H., Arihiro, K., Fujihara, M., Nishisaka, T., Sasaki, N., Sadahira, Y., Kimura A.
  • Organizer: 51^<th> Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2009-12-05
• [Presentation] Six Month Treatment of Low Dose Eltrombopag Is Efficatcious in Japanese Patients with Refractory Chronic Immune Thrombocytopenic Purpura(ITP). (2009)
  • Author(s): Tomiyama Y, et al
  • Organizer: 51^<th> Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2009-12-05
• [Presentation] AML1/RUNX1 Point Mutation Possibly Promotes Leukemic Transformation in Myelouroliferative Disorders. (2009)
  • Author(s): Imagawa J, et al
  • Organizer: 51^<th> Annual Meeting of the American Society of Hematology
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2009-12-05
• [Presentation] Results of Phase II Clinical Study of Lenalidomide in Japanese Patients with Myelodysplastic Syndrome (MDS). (2009)
  • Author(s): Harada H, Watanabe M, Suzuki K, Yanagita S, Suzuki T, Yoshida Y, Kimura A, Tsudo M, Takatoku M, Ozawa K
  • Organizer: The 10th International Symposium on Myelodysplastic Syndromes
  • Place of Presentation: Patras, Greece
  • Year and Date: 2009-05-07
• [Presentation] BMI-1 and AML-1 Point Mutation in the Pathogenesis of MDS. (2009)
  • Author(s): 木村昭郎
  • Organizer: The 10th International Symposium on Myelodysplastic Syndromes
  • Place of Presentation: Patras, Greece
  • Year and Date: 2009-05-07
• [Presentation] BMI-1 and AML-1 Point Mutation in the Pathogenesis of MDS. (2009)
  • Author(s): Kimura A
  • Organizer: 10^<th> International Symposium on Myelodysplastic Syndromes
  • Place of Presentation: パトラ Greece
  • Year and Date: 2009-05-07
• [Presentation] Results of Phase II Clinical Study of Leunalidomide in Japanese Patients with Myelodysplastic Syndrome(MDS). (2009)
  • Author(s): Harada H, et al
  • Organizer: 10^<th> International Symposium on Myelodysplastic Syndromes
  • Place of Presentation: パトラ Greece
  • Year and Date: 2009-05-07
• [Presentation] C/EBP a 変異パターンによる急性骨髄性白血病および骨髄異形成症候群の病型解析. (2008)
  • Author(s): 今川 潤
  • Organizer: 第105回日本内科学会総会
  • Place of Presentation: 東京
  • Year and Date: 2008-04-11
• [Book] 第9版 新臨床内科学(Practice of Internal Medicine 9th Edition) (2009)
  • Author(s): 木村昭郎
  • Total Pages: 1881
  • Publisher: 医学書院
• [Book] 血液疾患診療ハンドブック-診療の手引と臨床データ集- (2009)
  • Author(s): 田中英夫、木村昭郎
  • Total Pages: 671
  • Publisher: 医薬ジャーナル社
• [Book] 血液疾患診療ハンドブック (2009)
  • Author(s): 田中英夫、木村昭郎
  • Total Pages: 671
  • Publisher: 医薬ジャーナル社
• [Book] 新臨床内科学 (2009)
  • Author(s): 木村昭郎
  • Total Pages: 1881
  • Publisher: 医学書院