Molecular mechanism of refractoriness of myeloma mediated by adhesion molecules

粘附分子介导的骨髓瘤难治性的分子机制

• 批准号: 23591409
• 负责人: IMAI Yoichi
• 金额: $ 3.33万
• 依托单位: Tokyo Women's Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591409/
• 关键词: 血液腫瘍学; 多発性骨髄腫; 接着分子; カルシニューリン; 国際情報交換; インテグリン; CXCR4; HDAC阻害剤; HOXA9; 増殖抑制; アポトーシス

Multiple myeloma is one of incurable hematological malignancies. We revealed that functional inhibition of integrin and histone deacetylase (HDAC) blocks proliferation and induces apoptosis in myeloma cells. We discovered that MLL-HOXA9 and PPP3CA, alfa subunit of calcineurin, are inhibited by HDAC inhibitors. We revealed that MLL and PPP3CA are protected from protein degradation by HSP90. HDAC inhibitors induce degradation of MLL and PPP3CA through inhibition of chaperone function of HSP90. It was shown that PPP3CA plays important roles in maintenance of viability of myeloma cells in vitro and in vivo. In clinical samples, PPP3CA expression was high in advanced disease. Osteoclasts formation is essential for osteolytic disease of multiple myeloma. PPP3CA was necessary for formation of osteoclasts and HDAC inhibitors were shown to inhibit osteoclasts formation.

多发性骨髓瘤是一种无法治愈的血液系统恶性肿瘤。我们发现，整合素和组蛋白脱乙酰酶(HDAC)的功能抑制阻止了骨髓瘤细胞的增殖和诱导其凋亡。我们发现钙调神经磷酸酶α亚基MLL-HOXA9和PPP3CA被HDAC抑制剂抑制。我们发现，MLL和PPP3CA受到HSP90的保护，不会被蛋白质降解。HDAC抑制剂通过抑制HSP90的伴侣功能诱导MLL和PPP3CA的降解。结果表明，PPP3CA在维持骨髓瘤细胞的体内外活性方面起着重要作用。在临床标本中，PPP3CA在进展期高表达。破骨细胞的形成是多发性骨髓瘤溶骨性疾病的关键。PPP3CA是破骨细胞形成所必需的，而HDAC抑制剂被证明能抑制破骨细胞的形成。

项目成果

Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity.

• DOI: 10.1084/jem.20110447
• 发表时间: 2011-11-21
• 期刊: The Journal of experimental medicine
• 作者: Kataoka K;Sato T;Yoshimi A;Goyama S;Tsuruta T;Kobayashi H;Shimabe M;Arai S;Nakagawa M;Imai Y;Kumano K;Kumagai K;Kubota N;Kadowaki T;Kurokawa M
• 通讯作者: Kurokawa M

Transient lupus anticoagulant with a prolonged activated partial thromboplastin time secondary to cytomegalovirus-related infectious mononucleosis.

短暂性狼疮抗凝剂，可延长继发于巨细胞病毒相关传染性单核细胞增多症的活化部分凝血活酶时间。

• DOI: 10.1007/s00277-012-1532-0
• 发表时间: 2013
• 期刊: Ann Hematol.
• 作者: Shimura H;Imai Y;Ieko M;Shiseki M;Mori N;Teramura M;Motoji T.
• 通讯作者: Motoji T.

MLL-HOXA9 and calcineurin are novel therapeutic targets in multiple myeloma

MLL-HOXA9 和钙调神经磷酸酶是多发性骨髓瘤的新治疗靶点

• 发表时间: 2012
• 期刊: American Society of Hematology annual meeting abstracts
• 作者: Imai Y;Ohta E;Wang Y;Kitagawa Y;Ding Y;Yamada O;Maru Y;Motoji T
• 通讯作者: Motoji T

Combined romiplostim and intravenous immunoglobulin therapy increased platelet count, facilitating splenectomy in a patient with refractory immune thrombocytopenic purpura unresponsive to monotherapy

romiplostim 和静脉注射免疫球蛋白联合治疗可增加血小板计数，促进对单一疗法无反应的难治性免疫性血小板减少性紫癜患者的脾切除术

• 发表时间: 2012
• 期刊: British Journal of Haematology
• 影响因子: 6.5
• 作者: Mitsuhashi K;Ishiyama M;Imai Y;Shiseki M;Mori N;Teramura M;Seshimo A;Motoji T
• 通讯作者: Motoji T

The effect of iron overload and chelation on erythroid differentiation

• DOI: 10.1007/s12185-011-0988-3
• 发表时间: 2012-02-01
• 期刊: INTERNATIONAL JOURNAL OF HEMATOLOGY
• 影响因子: 2.1
• 作者: Taoka, Kazuki;Kumano, Keiki;Kurokawa, Mineo
• 通讯作者: Kurokawa, Mineo