Abstract
T cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course. Cytogenetic analysis, whole-exome and whole-genome sequencing have identified primary structural alterations in T-PLL, including inversion, translocation and copy number variation. Recurrent somatic mutations were also identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. Epigenetic alterations are the hallmark of many cancers. However, genome-wide epigenomic profiles have not been reported in T-PLL, limiting the mechanistic study of its carcinogenesis. We hypothesize epigenetic mechanisms also play a key role in T-PLL pathogenesis. To systematically test this hypothesis, we generated genome-wide maps of regulatory regions using H3K4me3 and H3K27ac ChIP-seq, as well as RNA-seq data in both T-PLL patients and healthy individuals. We found that genes down-regulated in T-PLL are mainly associated with defense response, immune system or adaptive immune response, while up-regulated genes are enriched in developmental process, as well as WNT signaling pathway with crucial roles in cell fate decision. In particular, our analysis revealed a global alteration of regulatory landscape in T-PLL, with differential peaks highly enriched for binding motifs of immune related transcription factors, supporting the epigenetic regulation of oncogenes and genes involved in DNA damage response and T-cell activation. Together, our work reveals a causal role of epigenetic dysregulation in T-PLL.
Highlights
T cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course
Through total RNA and mRNA sequencing we identified 1672 and 2364 genes differentially expressed between T-PLL and normal samples, including TCL1A, ATM and several T-cell receptor regulators that are known to play key roles in T-PLL pathogenesis
T-PLL was best characterized by oncogenic expression of TCL1A and dysfunction of ATM5
Summary
T cell prolymphocytic leukemia (T-PLL) is a rare disease with aggressive clinical course. Recurrent somatic mutations were identified in genes encoding chromatin regulators and those in the JAK-STAT signaling pathway. We hypothesize epigenetic mechanisms play a key role in T-PLL pathogenesis. To systematically test this hypothesis, we generated genome-wide maps of regulatory regions using H3K4me[3] and H3K27ac ChIP-seq, as well as RNA-seq data in both T-PLL patients and healthy individuals. Our analysis revealed a global alteration of regulatory landscape in T-PLL, with differential peaks highly enriched for binding motifs of immune related transcription factors, supporting the epigenetic regulation of oncogenes and genes involved in DNA damage response and T-cell activation. A lack of genome-wide epigenetic data has limited the investigation of the involvement of epigenetic mechanisms in this deadly disease
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