Small peptide targeting ANP32A as a novel strategy for acute myeloid leukemia therapy

ABSTRACT: Highlights • 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.

SUBMITTER: Wang M 

PROVIDER: S-EPMC8529559 | biostudies-literature |

REPOSITORIES: biostudies-literature