An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression

Abstract

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 (<i>P</i> < 0.001) and mitotic age (<i>P</i> < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely <i>TLX3, HOXA9, HOXA10</i>, and <i>NKX2-1</i>, and novel genes in T-ALL biology including <i>PLCB4, PLXND1</i>, and <i>MYO18B</i>. The CIMP− subgroup, with worse prognosis, was associated with higher expression of <i>TAL1</i> along with frequent STIL-TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP−), as well as stronger expression of <i>BEX1</i>. 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.