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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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  • Zahra Haider
  • Pär Larsson
  • Mattias Landfors
  • Linda Köhn
  • Kjeld Schmiegelow
  • Trond Flaegstad
  • Jukka Kanerva
  • Mats Heyman
  • Magnus Hultdin
  • Sofie Degerman
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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.

Original languageEnglish
JournalCancer Medicine
Volume8
Issue number1
Pages (from-to)311-324
Number of pages14
ISSN2045-7634
DOIs
Publication statusPublished - 2019

ID: 59083533