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PAX5–PML acts as a dual dominant-negative form of both PAX5 and PML

机译：PAX5-PML作为PAX5和PML的双重显性负性形式

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PAX5 is a transcription factor required for B-cell development and maintenance. PML is a tumor suppressor and a pro-apoptotic factor. A fusion gene, PAX5鈥揚ML, was found in acute lymphoblastic leukemia (ALL) with chromosomal translocation t(9;15)(p13;q24), but no functional analysis has been reported. Here, we demonstrate that PAX5鈥揚ML had a dominant-negative effect on both PAX5 and PML. PAX5鈥揚ML dominant negatively inhibited PAX5 transcriptional activity in the luciferase reporter assay and suppressed the expression of the PAX5 transcriptional targets in B-lymphoid cell line. Surprisingly, PAX5鈥揚ML hardly showed DNA-binding activity in vitro although it retained the DNA-binding domain of PAX5. Additional experiments, including chromatin immunoprecipitation (ChIP) assay, suggested that PAX5鈥揚ML bound to the promoter through the association with PAX5 on the promoter. On the other hand, coexpression of PAX5鈥揚ML inhibited PML sumoylation, disrupted PML nuclear bodies (NBs), and conferred apoptosis resistance on HeLa cells. Furthermore, treatment with arsenic trioxide (ATO) induced PML sumoylation and reconstitution of PML NBs, and overcame the anti-apoptotic effect of PAX5鈥揚ML in HeLa cells. These data suggest the possible involvement of this fusion protein in the leukemogenesis of B-ALL in a dual dominant-negative manner and the possibility that ALL with PAX5鈥揚ML can be treated with ATO.
机译：PAX5是B细胞发育和维持所需的转录因子。 PML是一种肿瘤抑制因子和促凋亡因子。在具有染色体易位t（9; 15）（p13; q24）的急性淋巴细胞白血病（ALL）中发现了一个融合基因PAX5-ML，但没有功能分析的报道。在这里，我们证明PAX5'-ML对PAX5和PML均具有显性负作用。在萤光素酶报告基因测定中，PAX5'_ML显性负抑制PAX5转录活性，并抑制B淋巴样细胞系中PAX5转录靶标的表达。出人意料的是，尽管PAX5'-ML保留了PAX5的DNA结合结构域，但在体外几乎不显示DNA结合活性。包括染色质免疫沉淀（ChIP）测定在内的其他实验表明，PAX5'-ML通过与启动子上的PAX5结合而与启动子结合。另一方面，PAX5-/-ML的共表达抑制了PML的磺酰化，破坏了PML核体（NBs），并赋予HeLa细胞凋亡抗性。此外，用三氧化二砷（ATO）处理可诱导PML磺酰化和PML NBs重建，并克服了PAX5-扬ML在HeLa细胞中的抗凋亡作用。这些数据表明该融合蛋白可能以双重显性-负性方式参与B-ALL的白血病发生，并且可能用ATO治疗具有PAX5'-扬ML的ALL。

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