Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas
By Teresa Palomero, L. Couronné, Hossein Khiabanian, Mi-Yeon Kim, A. Ambesi-Impiombato, A. Pérez-García, Z. Carpenter, F. Abate, Maddalena Allegretta, J. E. Haydu and 11 more. Nature Genetics, 2014
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Peripheral T cell lymphomas (PTCLs) are a heterogeneous and poorly understood group of non-Hodgkin lymphomas. Here we combined whole-exome sequencing of 12 tumor-normal DNA pairs, RNA sequencing analysis and targeted deep sequencing to identify new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DNMT3A and IDH2 as well as a new highly prevalent RHOA mutation encoding a p.Gly17Val alteration present in 22 of 35 (67%) angioimmunoblastic T cell lymphoma (AITL) samples and in 8 of 44 (18%) PTCL, not otherwise specified (PTCL-NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated guanine-exchange factor (GEF) proteins. In addition, we describe new and recurrent, albeit less frequent, genetic defects including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.
Subfields: Hematology, Molecular Biology, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/b7476ecc187c0d4daf79cb45eb9df7aada445b5e
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Citations in the corpus
- Binding of RHOA G17V to p300 enhances its HAT activity: a new mechanism of epigenetic deregulation in TFH lymphoma (2025, neutral): “Several studies provided evidence that RHOA G17V cannot bind GTP and has a dominant-negative effect on GTPase function of the endogenous protein, 12,14,19-21 but how RHOA G17V contributes to lymphomagenesis remains controversial.”
- Role of TET enzymes in DNA methylation, development, and cancer (2016, background): “2014); STAG2, DNAH9, and serine–threonine kinasemutations inAML patients (CancerGenome Atlas Research Network 2013); and RHOA, IDH2, and DNMT3A mutations in AITL patients (Palomero et al. 2014; Sakata-Yanagimoto et al. 2014).”
- The 2016 revision of the World Health Organization classification of lymphoid neoplasms. (2016, background): “These studies have identified mutations of epigenetic mediators (KMT2D [MLL2], TET2, KDM6A, ARID1B, DNMT3A, CREBBP, MLL, and ARID2), genes involved in signaling pathways (TNFAIP3,APC,CHD8,ZAP70,NF1,TNFRSF14,TRAF3), and tumor suppressors (TP53, FOXO1, BCORL1, ATM).(98)”