Small peptide targeting ANP32A as a novel strategy for acute myeloid leukemia therapy.
Small peptide targeting ANP32A as a novel strategy for acute myeloid leukemia therapy.
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靶向 ANP32A 的小肽作为急性髓系白血病治疗的新策略。
DOI：
10.1016/j.tranon.2021.101245
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发表时间：
2022-01
影响因子：
5
通讯作者：
Huang Z
中科院分区：
文献类型：
--
作者：
Wang M;Guo H;Zhang X;Wang X;Tao H;Zhang T;Peng M;Zhang M;Huang Z
H3 BP通过竞争性破坏ANP 32A和H3的相互作用，降低H3乙酰化和脂质代谢基因的表达，靶向ANP 32A抗AML。表达的H3 BP-GFP和合成的TAT-H3 BP肽在体外破坏多个靶基因位点上的H3乙酰化，从而降低白血病细胞的增殖并引起凋亡。TAT-H3 BP在体内表现出有效的抗白血病功效：肿瘤内注射TAT-H3 BP肽显著减小了裸鼠皮下肿瘤的体积;移植有TAT-H3 BP预处理的6133/MPL W515 L细胞的AMKL小鼠显示出显著缓和的疾病负荷和延长的存活时间。TAT-H3 BP肽在AML患者中具有治疗潜力，因为微摩尔浓度的TAT-H3 BP肽有效地抑制来自AML患者的人原代白血病细胞的增殖和CFU。人原代AML细胞中的高ANP 32A水平与TAT-H3 BP肽的干预作用相关。急性髓系白血病（AML）的临床治疗仍不尽如人意，迫切需要新的治疗策略.近年来的研究发现ANP 32A是一种新的白血病预后不良的生物标志物，它通过增加H3乙酰化和脂质代谢基因的表达促进白血病的发生。因此，探讨以ANP 32A为靶点治疗白血病的新策略具有重要意义。为了靶向ANP 32A，我们鉴定了与ANP 32A竞争结合组蛋白3的肽（称为H3结合肽，H3 BP）。通过H3 BP-GFP融合蛋白的过表达破坏ANP 32A和H3的相互作用模拟ANP 32A敲低的作用，损害靶基因的多个位点上的H3乙酰化，降低增殖，并引起白血病细胞的凋亡。此外，合成的膜穿透肽TAT-H3 BP有效地进入白血病细胞，并表型模拟这种作用。在体内，TAT-H3 BP显示出有效的抗白血病功效：肿瘤内注射TAT-H3 BP显著减少裸鼠皮下肿瘤的体积，并且用TAT-H3 BP预处理的6133/MPL W515 L细胞移植的受体小鼠表现出改善的白血病负荷和延长的存活。值得注意的是，TAT-H3 BP有效抑制人原代急性髓细胞的增殖和集落形成单位，而不影响正常脐带血细胞。我们的研究结果表明，干预ANP 32A与H3的物理相互作用会损害ANP 32A的致癌性，可能是一种有前途的AML治疗策略。
H3BP targeted ANP32A against AML by competitively disrupting ANP32A and H3 interaction and decreasing H3 acetylation and the expression of lipid metabolism genes. Expressed H3BP-GFP and synthetic TAT-H3BP peptide impaired H3 acetylation on multiple locus of target genes that reduced proliferation and caused apoptosis of leukemia cells in vitro. TAT-H3BP exhibits potent efficacy against leukemia in vivo: Intra-tumor injection of TAT-H3BP peptide prominently diminished the volume of subcutaneous tumors in nude mice; AMKL mice engrafted with TAT-H3BP-pretreated 6133/MPL W515L cells displayed dramatically moderated disease burden and prolonged survival time. TAT-H3BP peptide possess a therapeutic potential in patients with AML for micromole concentration of TAT-H3BP peptide efficiently inhibited the proliferation and CFU of human primary leukemia cells from AML patients. High ANP32A levels in human primary AML cells correlate with the intervention effect of TAT-H3BP peptide. Clinic therapy of acute myeloid leukemia (AML) remains unsatisfactory that urges for development of novel strategies. Recent studies identified ANP32A as a novel biomarker of unfavorable outcome of leukemia, which promoted leukemogenesis by increasing H3 acetylation and the expression of lipid metabolism genes. It is of great significance to investigate whether targeting ANP32A is a novel strategy for leukemia therapy. To target ANP32A, we identified a peptide that competed with ANP32A to bind to histone 3 (termed as H3-binding peptide, H3BP). Disrupting ANP32A and H3 interaction by the overexpression of H3BP-GFP fusion protein mimicked the effect of ANP32A knockdown, impaired H3 acetylation on multiple locus of target genes, reduced proliferation, and caused apoptosis in leukemia cells. Furthermore, a synthesized membrane-penetrating peptide TAT-H3BP effectively entered into leukemia cells and phenocopied such effect. In vivo, TAT-H3BP showed potent efficacy against leukemia: Intra-tumor injection of TAT-H3BP significantly reduced the volume of subcutaneous tumors in nude mice and recipient mice engrafted with TAT-H3BP-pretreated 6133/MPL W515L cells exhibited ameliorated leukemia burden and prolonged survival. Noticeably, TAT-H3BP efficiently suppressed proliferation and colony-forming unit of human primary AML cells without affecting normal cord blood cells. Our findings demonstrate that intervening the physical interaction of ANP32A with H3 impairs the oncogenicity of ANP32A and may be a promising therapeutic strategy against AML.
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影响因子：
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