Journal Article

Epigenetic alteration contributes to the transcriptional reprogramming in T-cell prolymphocytic leukemia

Zhang, Pan, Lee, Jeong-Heon, Call, Timothy G., Klee, Eric W., Tian, Shulan, Yan, Huihuang, Kay, Neil E., Witzig, Thomas E., Kalmbach, Michael, Zhang, Henan, Ordog, Tamas, Ding, Wei, Slager, Susan L., Hampel, Paul J.

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/114 / 631/208 / Adaptive immunity / Carcinogenesis / Cell activation / Cell fate / Cellular Reprogramming - genetics / Chromatin / Copy number / Cytogenetics / DNA Copy Number Variations / DNA damage / DNA Damage - genetics / Epigenesis, Genetic - genetics / Epigenesis, Genetic - physiology / Epigenetics / Gene mapping / Gene regulation / Genome-Wide Association Study / Genomes / Humanities and Social Sciences / Humans / Immune response / Immune system / Leukemia / Leukemia, Prolymphocytic, T-Cell - genetics / Leukemia, Prolymphocytic, T-Cell - immunology / Leukemia, Prolymphocytic, T-Cell - pathology / Lymphocyte Activation - genetics / Lymphocytes T / multidisciplinary / Rare diseases / Regulatory sequences / Science / Science (multidisciplinary) / Signal transduction / T-Lymphocytes - immunology / Transcription factors / Transcription, Genetic - genetics / Translocation / Whole genome sequencing / Wnt protein / Wnt Signaling Pathway - physiology