Histone acetylation in childhood high-risk acute leukemia

儿童高危急性白血病中的组蛋白乙酰化

• 批准号: 15591096
• 负责人: GOI Kumiko
• 金额: $ 2.18万
• 依托单位: University of Yamanashi
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591096/
• 关键词: acute lymphoblastic leukemia; Histone deacetylase inhibitor; apoptosis; cell cycle arrest; differentiation; 脱メチル化剤; 分化誘導; HDAC inhibitor; apoptosis

Inhibitors of histone deacetylase (HDAC) have been shown to induce both apoptosis and cell cycle arrest in various tumor cells. Although there are several reports on the effect of HDAC inhibitors on myeloid and T-cell leukemia, few studies have performed on B-precursor acute lymphoblastic leukemia (ALL). In the present study, we extensively examined the biological effects of trichostatin A (TSA), a representative HDAC inhibitor, on B-precursor cell lines (11q23 translocation, Philadelphia chromosome, and others) and T-cell cell lines, and showed that both B-precursor and T-cell, but not myeloid, lines were very sensitive to TSA in both induction of apoptosis and cell cycle arrest. TSA with demethylating agent 5'aza also induced monocytic differentiation in 11q23 cell line, The apoptosis pathway was caspase-dependent and Western blot analysis revealed upregulation of Bak and downregulation of Bcl-XL. B-precursor cell lines showed G1 arrest accompanied by the p53-independent p21 upregulation with or without a decrease in the CDK4 expression, whereas T-cell lines showed G2 arrest accompanied by the CyclinB downregulation. TSA treatment also strongly induced downregulation of c-Myc in all of the B-precursor and T-cell lines. TSA might have a therapeutic potential for the treatment of these malignancies.

组蛋白脱乙酰酶(HDAC)抑制剂可诱导多种肿瘤细胞的凋亡和细胞周期停滞。虽然关于HDAC抑制剂对髓系白血病和T细胞白血病的影响有一些报道，但很少有关于B前体急性淋巴细胞白血病(ALL)的研究。在本研究中，我们广泛地研究了具有代表性的HDAC抑制剂曲古抑素A(TSA)对B-前体细胞系(11q23易位、Philadelphia染色体等)和T细胞系的生物学效应，结果表明，B-前体细胞系和T细胞系都对TSA非常敏感，但对髓系细胞不敏感。TSA加去甲基化剂5‘氮杂氮也可诱导11q23细胞向单核细胞分化，其凋亡途径依赖于caspase，Western印迹分析显示Bak表达上调，Bclxl表达下调。B-前体细胞系表现为G1期停滞，伴有P53非依赖性p21表达上调，CDK4表达下调，而T-细胞系表现为G2期停滞，并伴有CyclinB下调。TSA还强烈诱导所有B-前体细胞和T-细胞系c-Myc表达下调。TSA可能在治疗这些恶性肿瘤方面具有潜在的治疗潜力。

项目成果

TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells

• DOI: 10.1182/blood-2002-06-1770
• 发表时间: 2003-05-01
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Uno, K;Inukai, T;Nakazawa, S
• 通讯作者: Nakazawa, S

山梨大学小児科における造血幹細胞移植成績 特に急性白血病について

山梨大学儿科造血干细胞移植结果，特别是急性白血病

• 发表时间: 2004
• 期刊: 山梨医学 32
• 作者: 合井久美子;その他
• 通讯作者: その他

E2A転写因子の異常とALL

E2A转录因子异常和ALL

• 发表时间: 2004
• 期刊: 血液・腫瘍科 49
• 作者: 犬飼岳史;合井久美子;黒澤秀光;稲葉俊哉
• 通讯作者: 稲葉俊哉