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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Haider , Z , Larsson , P , Landfors , M , Köhn , L , Schmiegelow , K , Flægstad , T , Kanerva , J , Heyman , M , Hultdin , M & Degerman , S 2019 , ' An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression ' , Cancer medicine , vol. 8 , no. 1 , pp. 311-324 . https://doi.org/10.1002/cam4.1917

Title: An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression
Author: Haider, Zahra; Larsson, Pär; Landfors, Mattias; Köhn, Linda; Schmiegelow, Kjeld; Flægstad, Trond; Kanerva, Jukka; Heyman, Mats; Hultdin, Magnus; Degerman, Sofie
Contributor: University of Helsinki, Children's Hospital
Date: 2019-01
Language: eng
Number of pages: 14
Belongs to series: Cancer medicine
ISSN: 2045-7634
URI: http://hdl.handle.net/10138/298654
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 (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.
Subject: BEX1
DNA methylation
HOXA
pediatric acute lymphoblastic leukemia
TAL1
TUMOR-SUPPRESSOR GENE
MINIMAL RESIDUAL DISEASE
DELETIONS
PCR
TRANSLOCATION
DISRUPTION
MUTATIONS
LANDSCAPE
FREQUENCY
PATHWAYS
3122 Cancers
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