An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression
An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression
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DOI：
10.1002/cam4.1917
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发表时间：
2019-01-01
期刊：
影响因子：
4
通讯作者：
Degerman, Sofie
中科院分区：
文献类型：
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作者：
Haider, Zahra;Larsson, Par;Degerman, Sofie
将儿童t细胞急性淋巴细胞白血病（T-ALL）患者分为CIMP （CpG岛甲基化表型）亚组有可能改善当前的风险分层。为了研究这些CIMP亚组背后的生物学，我们对北欧儿童T-ALL患者的诊断样本进行了全基因组甲基化测序，然后进行了靶向外显子组测序、端粒长度测量和RNA测序。CIMP亚组与表观遗传调控因子的变异没有显著相关性。然而，CIMP+亚组预后较好，其复制史指标较长，包括端粒长度较短（P = 0.015），表观遗传年龄（P < 0.001）和有丝分裂年龄（P < 0.001）较老。此外，CIMP+亚组ANTP同源盒癌基因TLX3、HOXA9、HOXA10和NKX2-1以及T-ALL生物学中的新基因PLCB4、PLXND1和MYO18B的表达均显著增加。CIMP-亚组预后较差，TAL1的表达较高，并且频繁出现still -TAL1融合（CIMP+为2/40，CIMP-为11/24），BEX1的表达也较强。总之，我们的研究结果表明，T-ALL CIMP亚群的白血病转化途径不同，这是由不同的复制史和不同的甲基组和转录组谱所指示的。这些新发现可能导致新的治疗策略。
Classification of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T-ALL patients were characterized by genome-wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2-1, and novel genes in T-ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP- subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL-TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP-), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T-ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies.