Establishment of novel differentiation-inducing therapy for leukemia with hematopoietic growth factors and arsenic trioxide

造血生长因子和三氧化二砷新型白血病诱导分化疗法的建立

• 批准号: 13671083
• 负责人: KIZAKI Masahiro
• 金额: $ 2.62万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671083/
• 关键词: Arsenic trioxide; Cytokine; Leukemia; GM-CSF; Apoptosis; BMP; Myeloma; Differentiation; 造血因子; ヒ素; 細胞分化; マウスモデル; Jak2キナーゼ

Arsenic trioxide (As_2O_3) effectively induces clinical remission via apoptosis in related acute promyelocytic leukemia (APL). However, because this new anti-leukemic drug is also considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. We investigated both in vitro and in vivo, the effects of a combination of As_2O_3 and GM-CSF as a novel therapeutic approach for the treatment of acute leukemia. Treatment of acute lmyeloid eukemic cells with a combination of As_2O_3 and GM-CSF for 4 days resulted in differentiation, but not apoptosis, to mature granulocytes. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in acute promyelocytic leukemia (APL) cells, and a specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of As_2O_3-treated APL cells. In in vivo analysis, As_2O_3 induced differentiation of APL cells in a retinoic aci … More d-resistant APL model of human GM-CSF-producing transgenic SCID mice that had a high level of human GM-CSF in their sera. In contrast, As_2O_3 alone diminished tumors in retinoic acid-resistant APL UF-1 cells transplanted into NOD/SCID mice via induction of apoptosis.We also performed the experiments using TGF-β superfamily cytokines including bone morphogenetic protein(BMP) and activin A for inducing apoptosis of leukemia and myeloma cells. BMP induces apoptosis of human myeloma cell lines and primary samples. BMP caused cell cycle arrest in the G1 phase which was associated with accumulation of p21 and p27, and the subsequent apoptosis of myeloma cells. BMP also induced down-regulation of Bcl-X_L through the inactivation of STAT3, resulting in the induction of apoptosis of myeloma cells. In addition, activin A induced rapid apoptosis of chronic myeloid leukemia (CML) cells via transient induction of Mcl-1. These results suggest that cytokines may have a potential to be novel therapeutic agents for treatment in patients with leukemia and myeloma. Especially, a combination of As_2O_3 and GM-CSF appears to be a novel differentiation-inducing therapy for APL with less toxic effects. Less

三氧化二砷 (As_2O_3) 通过细胞凋亡有效诱导相关急性早幼粒细胞白血病 (APL) 的临床缓解。然而，由于这种新的抗白血病药物也被认为是一种毒物，其可能的不良反应是与其临床使用相关的一个非常重要的问题。我们在体外和体内研究了 As_2O_3 和 GM-CSF 组合作为治疗急性白血病的新方法的效果。用As_2O_3和GM-CSF组合处理急性粒细胞白血病细胞4天，导致分化为成熟粒细胞，但没有凋亡。 GM-CSF被发现与急性早幼粒细胞白血病（APL）细胞中Jak2激酶酪氨酸磷酸化增加有关，而Jak2的特异性抑制剂AG490完全阻断了GM-CSF阻止As_2O_3处理的APL细胞凋亡和诱导分化的能力。在体内分析中，As_2O_3 在产生人 GM-CSF 的转基因 SCID 小鼠的视黄酸 aci 抗性 APL 模型中诱导 APL 细胞分化，这些小鼠的血清中含有高水平的人 GM-CSF。相比之下，单独使用As_2O_3可以通过诱导细胞凋亡来减少移植到NOD/SCID小鼠体内的抗视黄酸APL UF-1细胞中的肿瘤。我们还进行了使用TGF-β超家族细胞因子包括骨形态发生蛋白（BMP）和激活素A诱导白血病和骨髓瘤细胞凋亡的实验。 BMP 诱导人骨髓瘤细胞系和原代样品的凋亡。 BMP 导致细胞周期停滞在 G1 期，这与 p21 和 p27 的积累以及随后的骨髓瘤细胞凋亡有关。 BMP还通过STAT3失活诱导Bcl-X_L下调，从而诱导骨髓瘤细胞凋亡。此外，激活素 A 通过短暂诱导 Mcl-1 诱导慢性粒细胞白血病 (CML) 细胞快速凋亡。这些结果表明细胞因子可能有潜力成为治疗白血病和骨髓瘤患者的新型治疗剂。特别是，As_2O_3 和 GM-CSF 的组合似乎是一种新型的 APL 分化诱导疗法，且毒性作用较小。较少的

项目成果

Takayama N, Kizaki M, et al.: "A novel mutation of PML/RARα chimeric gene exhibits dramatically decreased ligand-binding activity and confers acquired resistance to RA in APL"Exp. Hematol.. 29. 864-872 (2001)

Takayama N、Kizaki M 等人：“PML/RARα 嵌合基因的一种新突变表现出显着降低的配体结合活性，并赋予 Hematol 获得性 RA 抗性”Exp. 29. 864-872 (2001)

Fukuchi Y, Kizaki M, et al: "Mcl-1, an early-induction molecule, modulates activin A-induced apoptosis and differentiation of CML cells"Oncogene. 20(6). 704-713 (2001)

Fukuchi Y、Kizaki M 等人：“Mcl-1，一种早期诱导分子，调节激活素 A 诱导的 CML 细胞凋亡和分化”癌基因。

Hirano T, Kizaki M, Kato K, et al.: "Enhancement of sensitivity by bestatin of acute promyelocytic leukemia NB4 cells to all-trans retinoic acid"Leuk. Res.. 26(12). 1097-1103 (2002)

Hirano T、Kizaki M、Kato K 等人：“急性早幼粒细胞白血病 NB4 细胞的贝他汀对全反式视黄酸的敏感性增强”Leuk。

Suwanai H, Matsushita H, Kizaki M, et al.: "A novel therapeutic technology of specific RNA inhibition for APL : Improved design of maxizymes against PML/RARα mRNA"Int. J. Oncol.. 20. 127-130 (2002)

Suwanai H、Matsushita H、Kizaki M 等人：“APL 特异性 RNA 抑制的新颖治疗技术：针对 PML/RARα mRNA 的大酶的改进设计”Int. J. Oncol.. 20. 127-130 (2002)

Ito K, Kinjo K, Nakazato T, Ikeda Y and Kizaki M: "Expression and sequence analyses of p33^<ING1> gene in myeloid leukemia"American Journal of Hematology. 69(2). 141-143 (2002)

Ito K、Kinjo K、Nakazato T、Ikeda Y 和 Kizaki M：“骨髓性白血病中 p33^<ING1> 基因的表达和序列分析”美国血液学杂志。