Identification of new therapeutic target for MLL rearranged acute myeloid leukemia

MLL重排急性髓系白血病新治疗靶点的鉴定

• 批准号: 23591547
• 负责人: IMAMURA Toshihiko
• 金额: $ 3.33万
• 依托单位: Kyoto Prefectural University of Medicine
• 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-23591547/
• 关键词: AML; ATRA; LSD1; H3K4me2; MLL; C/EBPA; 分化誘導; LSD1阻害剤; mTOR阻害剤; RARA; 急性骨髄性白血病; レチノイン酸; MLL遺伝子; 分化誘導療法

This study revealed the potential mechanism of high ATRA sensitivity of MLL-AF9-positive AML compared to MLL-AF4-positive AML. The level of dimethyl histone H3 lysine 4 (H3K4me2) in the RARA gene-promoter region, PU.1 upstream regulatory region (URE) and RUNX1 +24/+25 intronic enhancer was higher in MLL-AF9-positive cells than in MLL-AF4-positive cells, and inhibiting lysine-specific demethylase 1 (LSD1), which acts as a histone demethylase inhibitor, reactivated ATRA sensitivity in MLL-AF4-positive cell. These findings suggest that the level of H3K4me2 in the RARA gene-promoter region, PU.1 URE and RUNX1 intronic enhancer is determined by the MLL-fusion partner. Our findings provide insight into the mechanisms of ATRA sensitivity in AML and novel treatment strategies for ATRA-resistant AML.

本研究揭示了MLL-AF9阳性AML较MLL-AF4阳性AML对ATRA敏感性高的潜在机制。在MLL-AF9阳性细胞中，RARA基因启动子区、PU.1上游调控区(URE)和RUNX1+24/+25内含子增强子的二甲基组蛋白H3赖氨酸4(H3K4me2)水平高于MLL-AF4阳性细胞，抑制赖氨酸特异性去甲基酶1(LSD1)可重新激活MLL-AF4阳性细胞对ATRA的敏感性。这些发现表明，RARA基因启动子区域、PU1URE和RUNX1内含子增强子的H3K4me2水平是由MLL融合伙伴决定的。我们的研究结果为AML对ATRA的敏感性机制和对ATRA耐药的AML提供了新的治疗策略。

项目成果

MLL-AF9 positive acute myeloid leukemia cells are sensitive to all-trans retinoic acid.

MLL-AF9阳性急性髓系白血病细胞对全反式视黄酸敏感。

• 发表时间: 2013
• 作者: Sakamoto K;Imamura T;Yano M;Yoshida H;Fujiki A;Hirashima Y;Hosoi H.
• 通讯作者: Hosoi H.

GATA-2 anomaly and clinical phenotype of a sporadic case of lymphedema, dendritic cell, monocyte, B- and NK-cell (DCML) deficiency, and myelodysplasia

• DOI: 10.1007/s00431-012-1715-7
• 发表时间: 2012-08-01
• 期刊: EUROPEAN JOURNAL OF PEDIATRICS
• 影响因子: 3.6
• 作者: Ishida, Hiroyuki;Imai, Kosuke;Nonoyama, Shigeaki
• 通讯作者: Nonoyama, Shigeaki

LSD1 inhibitor activates retinoic acid pathway in MLL fusion positive acute myeloid leukemia

LSD1抑制剂激活MLL融合阳性急性髓系白血病的视黄酸通路

• 发表时间: 2012
• 作者: Yano M;Imamura T;Sakamoto K;Yoshida H;Fujiki A;Hirashima Y;Ishida H;Hosoi H.
• 通讯作者: Hosoi H.

LSD1 inhibitor activates retinoic acid pathway in MLL fusion positive acute myeloid leukemia.

LSD1 抑制剂激活 MLL 融合阳性急性髓系白血病中的视黄酸途径。

• 发表时间: 2012
• 作者: Yano M;Imamura T;Sakamoto K;Yoshida H;Fujiki A;Hirashima Y;Ishida H;Hosoi H.
• 通讯作者: Hosoi H.

MLL-AF9陽性急性骨髄性白血病細胞はATRA感受性を示す

MLL-AF9阳性急性髓系白血病细胞表现出ATRA敏感性

• 发表时间: 2013
• 作者: Ogura M;Urabe M;Akimoto T;Onishi A;Ito C;Ito T;Tsukahara T;Mizukami H;Kume A;Muto S;Kusano E;and Ozawa K.;坂本謙一,今村俊彦,矢野未央,吉田秀樹,藤木敦,平嶋良章,細井創
• 通讯作者: 坂本謙一,今村俊彦,矢野未央,吉田秀樹,藤木敦,平嶋良章,細井創