Development of the new treatment strategy of ATRA-resistant APL using PP2A-FOXO3A activation pathway

利用PP2A-FOXO3A激活途径开发ATRA耐药APL的新治疗策略

• 批准号: 23591407
• 负责人: KOMATSU NORIO
• 金额: $ 3.41万
• 依托单位: Juntendo 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-23591407/
• 关键词: FOXO3A; プロテインホスファターゼ2A; 急性前骨髄球性白血病(APL); 全トランスレチノイン酸(ATRA); ATRA耐性; FTY720; 活性酸素種; APL; ATRA; sodium selenate; PP2A; FOXO3a; apoptosis

Acute promyelotic leukemia (APL) patients usually respond to all-trans retinoic acid (ATRA) treatment, however, some patients are refractory and resistant to ATRA. Therefore, an alternative strategy to treat APL patients is demanded. Here, we showed that FTY720, an immunosuppressive drug, is capable of inducing apoptosis in both ATRA-sensitive and & -resistant APL cells in vitro and regresses tumor mass generated from ATRA-resistant APL cells in vivo. This demonstrates its capability as a potential therapeutic compound in APL treatment. In addition, we have shown that N-acetylcysteine (NAC) rescues FTY720-dependent apoptosis induction in NB4 cells, implying that FTY720 cytotoxic effect to NB4 cells are due at least partly if not all, to a generation of reactive oxygen species (ROS). These observations demonstrate a potential of FTY720 as a therapeutic compound against APL irrespective of whether it is resistant to ATRA.

急性前临床白血病（APL）患者通常对全反式视黄酸（ATRA）治疗反应，但是，有些患者对ATRA具有抵抗力且对ATRA有抵抗力。因此，需要一种治疗APL患者的替代策略。在这里，我们表明，一种免疫抑制药物FTY720能够在体外诱导对ATRA敏感的APL细胞的凋亡，并在体外诱导ATRA抗APL细胞产生的肿瘤质量。这证明了它作为APL治疗中潜在的治疗化合物的能力。此外，我们已经表明，N-乙酰半胱氨酸（NAC）在NB4细胞中挽救了FTY720依赖性凋亡诱导，这表明FTY720对NB4细胞的细胞毒性作用至少在不全部（如果不是全部）到期，这是由于一系列反应性氧气（ROS）。这些观察结果证明了FTY720作为治疗化合物的潜力，而不论其对ATRA是否具有抗性。

项目成果

Analysis of JAK2V617F downstream signaling

JAK2V617F下游信号传导分析

• 发表时间: 2013
• 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;Ei Leen Liew
• 通讯作者: Ei Leen Liew

A highly sensitive and reliable JAK2V617F detection method for the diagnostics of MPN

一种用于 MPN 诊断的高度灵敏且可靠的 JAK2V617F 检测方法

• 发表时间: 2013
• 作者: Nishimoto N;Arai S;Ichikawa M;Nakagawa M;Goyama S;Kumano K;Takahashi T;Kamikubo Y;Imai Y;Kurokawa M;.Soji Morishita
• 通讯作者: .Soji Morishita

Granulocytic differentiation in leukemia cells by the inhibition of histone deacetylase SIRT2

抑制组蛋白脱乙酰酶 SIRT2 导致白血病细胞粒细胞分化

• 发表时间: 2013
• 作者: Mitsuhashi K;Ishiyama M;Imai Y;Shiseki M;Mori N;Teramura M;Seshimo A;Motoji T;Yoshitaka Sunami
• 通讯作者: Yoshitaka Sunami

Rituximab Activates Syk and Akt in Cd20-Positive B Cell Lymphoma Cells Dependent on Cell Membrane Cholesterol Levels

利妥昔单抗根据细胞膜胆固醇水平激活 Cd20 阳性 B 细胞淋巴瘤细胞中的 Syk 和 Akt

• DOI: 10.1016/j.exphem.2013.04.006
• 发表时间: 2013
• 期刊: Exp Hematol
• 影响因子: 2.6
• 作者: Nozaki Y; Mitsumori T;Yamamoto T;Kawashima I ;Shobu Y;Hamanaka S;Nakajima K;Komatsu N;Kirito K
• 通讯作者: Kirito K

Computational dissection of distinct microRNA activity signatures associated with peripheral T cell lymphoma subtypes

与外周 T 细胞淋巴瘤亚型相关的不同 microRNA 活性特征的计算剖析

• DOI: 10.1038/leu.2013.121
• 发表时间: 2013
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: 出 勝;古場慎一;長野由美;荒金尚子;佐藤明美;三砂範幸;成澤 寛;木村晋也;末岡榮三朗;Suzuki HI
• 通讯作者: Suzuki HI