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DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jesus Duque, Michael Lübbert, Mark Kirschbaum
Interestingly, histone modifications are not only related to epigenetic regulation of transcription, but also cooperate with other proteins to regulate nuclear processes like DNA repair. Certain genes, with tumor suppressor properties such as p21WAF1, are silent at the transcriptional level in the absence of DNA hypermethylation and the presence of H3 and H4 hypoacetylation (77). Moreover, H3 acetylation is functionally linked to H3K4 trimethylation by the MLL4 protein, which has a very high homology to MLL1 gene. H3 acetylation determines the degree and the abundance of H3K4 methylation and this interaction plays an important role in the epigenetic response to the HDACis valproate and butyrate (78).
Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma
Published in OncoImmunology, 2021
Hua You, Zijun Y. Xu-Monette, Li Wei, Harry Nunns, Máté L. Nagy, Govind Bhagat, Xiaosheng Fang, Feng Zhu, Carlo Visco, Alexandar Tzankov, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D. Hsi, Fredrick B. Hagemeister, Jooryung Huh, Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B. Møller, Benjamin M. Parsons, J. Han Van Krieken, Miguel A. Piris, Jane N. Winter, Yong Li, Qingyan Au, Bing Xu, Maher Albitar, Ken H. Young
To understand the prognostic effect of high mutation numbers, we first compared the genetic features of MUThigh patients with MUTlow patients with DLBCL-NOS. Distribution of frequent (occurred in ≥7 patients) gene mutations in MUThigh patients is displayed in Figure 2(a), and genes more frequently mutated in MUThigh versus MUTlow patients are shown in Figure 2(b) (in overall DLBCL-NOS) and Supplementary Table 2 (in GCB/ABC subtypes). Notably, by function many genes over-represented in MUThigh patients are involved in epigenetic regulation (such as KMT2D, EZH2, CREBBP, TET2, SMARCA4, DNMT3A, EP300, KDM6A, and SMC3). The most enriched gene was KMT2D (also known as MLL2 or MLL4, encoding a histone methyltransferase for H3K4me; Figure 2(b-c)) in GCB (64.9% in MUThigh patients versus 26.7% in MUTlow patients) and TP53 in ABC DLBCLs (46.4% in MUThigh patients versus 16.1% in MUTlow patients (Supplementary Table 2). The most common type of KMT2D mutations was nonsense mutations (48.7%), followed by missense (32.4%) and frameshift (20.9%) and inframe INDEL (2.0%) mutations (Figure 2(b)), in contrast with the predominant missense type of TP53 mutations. KMT2D and TP53 were also recurrently mutated in HGBCL-MYC/BCL2-DH patients despite the small number of cases in our cohort (Figure 2(b)).