Histone acetylation in childhood high-risk acute leukemia

组蛋白去乙酰化酶（HDAC）抑制剂已被证明在各种肿瘤细胞中诱导凋亡和细胞周期阻滞。尽管有几篇关于HDAC抑制剂对髓细胞和T细胞白血病的影响的报道，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-阿司他丁A（TSA）对B-前体细胞系（11 q23易位、费城染色体等）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，而不是髓系，在诱导凋亡和细胞周期阻滞方面对TSA都非常敏感。TSA和去甲基化剂5 'aza也诱导11 q23细胞向单核细胞分化，凋亡途径依赖于caspase，Western blot分析显示巴克上调，Bcl-XL下调。B-前体细胞系表现出G1期阻滞，伴随着p53非依赖性p21上调，伴随或不伴随CDK 4表达的降低，而T-细胞系表现出G2期阻滞，伴随着CyclinB下调。TSA处理还强烈诱导所有B-前体和T-细胞系中c-Myc的下调。TSA可能具有治疗这些恶性肿瘤的治疗潜力。

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.