Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia.
Aberrant DNA Methylation Is Associated with a Poor Outcome in Juvenile Myelomonocytic Leukemia.
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DOI：
10.1371/journal.pone.0145394
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kojima S
中科院分区：
文献类型：
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作者：
Sakaguchi H;Muramatsu H;Okuno Y;Makishima H;Xu Y;Furukawa-Hibi Y;Wang X;Narita A;Yoshida K;Shiraishi Y;Doisaki S;Yoshida N;Hama A;Takahashi Y;Yamada K;Miyano S;Ogawa S;Maciejewski JP;Kojima S
幼年型粒单核细胞白血病（JMML）是骨髓增生异常/骨髓增殖性肿瘤的重叠，是一种难治性小儿骨髓肿瘤。转录的表观遗传调控，特别是 CpG 甲基化，在肿瘤进展中发挥着重要作用，主要是通过抑制肿瘤抑制基因。为了阐明异常 DNA 甲基化的临床重要性，我们通过亚硫酸氢盐转化和焦磷酸测序技术研究了 92 名 JMML 患者基因组中 16 个靶基因的高甲基化状态。在 16 个候选基因中，BMP4、CALCA、CDKN2A 和 RARB 在 72% (67/92) 的患者中表现出显着的高甲基化。根据高甲基化基因的数量，根据异常甲基化评分 (AMS) 0、1-2 或 3-4，将患者分为三组。在 AMS 0 队列中，5 年总生存率 (OS) 和无移植生存率 (TFS) 良好（分别为 69% 和 76%）。在 AMS 1-2 队列中，5 年 OS 与 AMS 0 队列 (68%) 相当，而 TFS 较差 (6%)。在 AMS 3-4 队列中，5 年 OS 和 TFS 明显较低（分别为 8% 和 0%）。表观遗传学分析为临床医生选择 JMML 患者的治疗策略提供了有用的信息。对于造血干细胞移植不能改善预后的AMS 3-4患者，应建立替代疗法，包括DNA甲基转移酶抑制剂和新的分子靶向药物作为治疗选择。
Juvenile myelomonocytic leukemia (JMML), an overlap of myelodysplastic / myeloproliferative neoplasm, is an intractable pediatric myeloid neoplasm. Epigenetic regulation of transcription, particularly by CpG methylation, plays an important role in tumor progression, mainly by repressing tumor-suppressor genes. To clarify the clinical importance of aberrant DNA methylation, we studied the hypermethylation status of 16 target genes in the genomes of 92 patients with JMML by bisulfite conversion and the pryosequencing technique. Among 16 candidate genes, BMP4, CALCA, CDKN2A, and RARB exhibited significant hypermethylation in 72% (67/92) of patients. Based on the number of hypermethylated genes, patients were stratified into three cohorts based on an aberrant methylation score (AMS) of 0, 1–2, or 3–4. In the AMS 0 cohort, the 5-year overall survival (OS) and transplantation-free survival (TFS) were good (69% and 76%, respectively). In the AMS 1–2 cohort, the 5-year OS was comparable to that in the AMS 0 cohort (68%), whereas TFS was poor (6%). In the AMS 3–4 cohort, 5-year OS and TFS were markedly low (8% and 0%, respectively). Epigenetic analysis provides helpful information for clinicians to select treatment strategies for patients with JMML. For patients with AMS 3–4 in whom hematopoietic stem cell transplantation does not improve the prognosis, alternative therapies, including DNA methyltransferase inhibitors and new molecular-targeting agents, should be established as treatment options.