Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL
Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL
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DOI：
10.1182/blood.2019004090
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发表时间：
2020-11-12
期刊：
影响因子：
20.3
通讯作者：
Inukai, Takeshi
中科院分区：
文献类型：
--
作者：
Watanabe, Atsushi;Miyake, Kunio;Inukai, Takeshi
核型是儿童B细胞前体急性淋巴细胞白血病(BCP-ALL)的重要预后因素，但其潜在的药物基因组学仍不清楚。天冬酰胺酶是目前儿童BCP-ALL化疗中不可或缺的组成部分。天冬酰胺酶治疗会耗尽血清天冬酰胺。正常的造血细胞可以通过天冬酰胺合成酶(ASNS)活性产生天冬酰胺，但所有细胞都不能合成足够量的天冬酰胺。ASNS基因在其启动子上有一个典型的CpG岛。因此，ASNS CpG岛甲基化可能是BCP-ALL中ASNS基因沉默的表观遗传学机制之一。为了深入了解天冬酰胺酶治疗的药物基因组学，我们调查了ASNS甲基化状态与天冬酰胺酶敏感性的关系。在正常造血细胞中，ASNS CpG岛基本上没有甲基化，但在BCP-ALL细胞中，它是等位基因特异性甲基化的。ASNS基因位于进化保守的印记基因簇7q21。儿童BCP-ALL的ASNS甲基化与7q21处印记基因簇的异常甲基化有关。在ETV6-RUNX1敲门小鼠的白血病脾样本中，也证实了小鼠ASN的异常甲基化和同线印记基因簇。在3个儿童BCP-ALL队列中，ASNS在BCP-ALL核型良好的患者中高度甲基化，但在BCP-ALL预后较差的患者中大多未甲基化。ASNS甲基化水平越高，BCP-ALL对L-天冬酰胺酶的敏感性越高，其机制可能与ASNS基因和蛋白表达水平降低有关。这些观察表明，由于异常印迹导致ASNS基因沉默是天冬酰胺酶治疗BCP-ALL白血病特异性活性的一种药物遗传学机制。(血。2020；136(20)：2319-2333)
Karyotype is an important prognostic factor in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), but the underlying pharmacogenomics remain unknown. Asparaginase is an integral component in current chemotherapy for childhood BCP-ALL. Asparaginase therapy depletes serum asparagine. Normal hematopoietic cells can produce asparagine by asparagine synthetase (ASNS) activity, but ALL cells are unable to synthesize adequate amounts of asparagine. The ASNS gene has a typical CpG island in its promoter. Thus, methylation of the ASNS CpG island could be one of the epigenetic mechanisms for ASNS gene silencing in BCP-ALL. To gain deep insights into the pharmacogenomics of asparaginase therapy, we investigated the association of ASNS methylation status with asparaginase sensitivity. The ASNS CpG island is largely unmethylated in normal hematopoietic cells, but it is allele-specifically methylated in BCP-ALL cells. The ASNS gene is located at 7q21, an evolutionally conserved imprinted gene cluster. ASNS methylation in childhood BCP-ALL is associated with an aberrant methylation of the imprinted gene cluster at 7q21. Aberrant methylation of mouse Asns and a syntenic imprinted gene cluster is also confirmed in leukemic spleen samples from ETV6-RUNX1 knockin mice. In 3 childhood BCP-ALL cohorts, ASNS is highly methylated in BCP-ALL patients with favorable karyotypes but is mostly unmethylated in BCP-ALL patients with poor prognostic karyotypes. Higher ASNS methylation is associated with higher L-asparaginase sensitivity in BCP-ALL through lower ASNS gene and protein expression levels. These observations demonstrate that silencing of the ASNS gene as a result of aberrant imprinting is a pharmacogenetic mechanism for the leukemia-specific activity of asparaginase therapy in BCP-ALL. (Blood. 2020; 136(20):2319-2333)