Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Leukemia. 2018 Jul;32(7):1587-1597. doi: 10.1038/s41375-018-0010-7. Epub 2018 Feb 2.
Deregulation of key regulators of histone modification is important in the initiation and progression of human leukemia. Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) participates in histone acetylation and its role in acute myeloid leukemia remains unclear. Here we observed significant upregulation of ANP32A in primary AML cells, which was essential for AML cell proliferation, survival, and colony formation. Integrative analysis of the genome-wide histone H3 acetylation and gene expression demonstrated that ANP32A deficiency reduced histone H3 acetylation, in accordance with changes in gene expression. Notably, significant histone H3 acetylation enrichment was associated with mRNA changes in lipid-related genes, including APOC1, PCSK9, P2RX1, and LPPR3. Indeed, over-expression of APOC1 partially compensated the proliferation-defect phenotype in ANP32A deficient AML cells while APOC1 knockdown alone mimicked the effect of ANP32A deficiency. Collectively, our data indicate that ANP32A is a novel regulator of histone H3 acetylation and promotes leukemogenesis.
组蛋白修饰关键调控因子的失调在人类白血病的发生和进展中具有重要意义。酸性亮氨酸丰富核磷蛋白 32A（ANP32A）参与组蛋白乙酰化，但其在急性髓系白血病中的作用尚不清楚。本研究观察到原发性 AML 细胞中 ANP32A 的显著上调，这对 AML 细胞的增殖、存活和集落形成至关重要。全基因组组蛋白 H3 乙酰化和基因表达的综合分析表明，ANP32A 缺失降低了组蛋白 H3 乙酰化，与基因表达的变化一致。值得注意的是，脂质相关基因（包括 APOC1、PCSK9、P2RX1 和 LPPR3）的 mRNA 变化与显著的组蛋白 H3 乙酰化富集相关。事实上，APOC1 的过表达部分补偿了 ANP32A 缺陷 AML 细胞的增殖缺陷表型，而单独的 APOC1 敲低则模拟了 ANP32A 缺陷的作用。综上所述，我们的数据表明 ANP32A 是组蛋白 H3 乙酰化的新型调节因子，促进了白血病的发生。
