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Rosette-Forming Glioneuronal Tumor
Published in Dongyou Liu, Tumors and Cancers, 2017
RGNT is thought to originate from progenitor pluripotential cells of the subependymal plate, capable of differentiating along both glial and neurocytic lines. The tumor is linked to the loss of 1p and gain of 1q, as well as gain of the whole chromosomes 7, 9, and 16. Local amplifications in 9q34.2 and 19p13.3 (encompassing the SBNO2 gene) and the presence of the KIAA1549:BRAF gene on chromosome 7 have been identified. Other mutations concern the IDH1 and IDH2, MLL2, CNNM3, PCDHGC4, SCN1A, and FGFR1 genes. MAPK pathway and methylome changes, driven by KIAA1549:BRAF fusion and MLL2 mutation, respectively, could be associated with the development of this rare tumor entity [7,8].
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Primarily, the H3K4me3 distribution is thoroughly coupled to CpG-dependent dinucleotide repeated units present in CpG islands. Predominately, unmethylated GC-dense DNA and CpG- regions are found at promoter regions in 50–70% of vertebrates [24]. The discovery of Zn-finger CxxC is usually found in SETD1A/B subunit CFP1 and in MLL1/2, which elucidated the presence of a biochemical link between promoters of CpGI and H3K4me3 [2] (Figure 3.3). Promoters of CPGI are marked with the presence of H3K4me3 strongly correlated to the activity of genes [25,26]. In addition, emerging evidence illustrates that MLL2 is highly responsible in order to maintain H3K4me3 in vivo at CpGI promoters along with reduce expression [27,28]. Although CEPI, a specific subunit of SETD1, is more preferentially enriched in the higher H3K4me3 levels and mostly found at the most of active regions of gene promoter [29]. CpGI promoters started showing linkage with them in regulated developmental genes, which possess bivalent structure and play a role in harboring the H3K4me3 repressive marks and H3K4me2 [30]. Interestingly, H3K4me3 writers’ ability to sample the genome of CpGI is wide. It has also been found that H3K4me3 presence at promoters of CpGI might act as poison for the silent genes that cause rapid activation of these genes upon differentiation. The binding in between the complex of SETD1/MLL might reinforce their strong binding by means of recognition of the presence of their specific own marks, such as H3K4me3. CFP1 having PHD finger domain, known explicitly for its role in H3K4me3 read, also found that it displays its potent role in mediating the interaction between SETDI and H3K4me3 [31–33]. In Hox Locus, the recruitment of MLLI to the specific target sites is usually carried out through the presence of MLL1 containing its third domain, which is more important in the case of H3K4me3 binding [34].
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)).
An analysis of genetic targets for guiding clinical management of follicular lymphoma
Published in Expert Review of Hematology, 2020
Ruth Alonso-Alonso, Marta Rodriguez, Daniel Morillo, Raul Cordoba, Miguel A Piris
Longitudinal analyses using NGS have also identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation [42,43]. Thus, point mutations in genes involved in epigenetic regulation and chromatin modification, including MLL2 (KMT2D), EZH2, CREBBP, EP300 and MEF2B, dominate the FL landscape [42–48], in which mutations in one or more chromatin-modifier genes are present in around 95% of patients. The frequency of mutations is as follows: KMT2D (60–90%), CREBBP (60–70%), EP300 (10–20%), EZH2 (20–30%) and ARIDIA (10–15%) [43,45–47,49-51]. KMT2D is atumor suppressor whose functional impairment causes an expansion of GC B-cells and promotes lymphomagenesis [43,45,50]. This gene encodes ahistone methyltransferase of H3K4 that is affected mainly by inactivating mutations.
Mantle cell lymphoma: insights into therapeutic targets at the preclinical level
Published in Expert Opinion on Therapeutic Targets, 2020
Epigenetic deregulation is a hallmark of MCL. Recurrent mutations of several established epigenetic regulators can be found in MCL patients including MLL2/KMT2D, MLL3/KMT2C, MEF2B, SMARCA4, NSD2, ARID1 [10,14]. Histone deacetylase inhibitors (HDACs) regulate expression of key molecules involved in pathogenesis and drug resistance of MCL including SOX11, proapoptotic BCL2 molecules or VEGF [149,150]. HDAC inhibitors provide an alternative strategy for combinatorial therapy of MCL [151]. Single-agent HDACs demonstrated only modest activity in MCL. Cladribine, an inhibitor of DNA methylation, is used in some centers in front-line or salvage therapy of MCL. The combination of cladribine, rituximab, and vorinostat has been recently tested in newly diagnosed MCL [152]. The combinations of HDAC inhibitors and ibrutinib appeared particularly promising in the preclinical settings. The efficacy of abexinostat and pevonedistat in combination with ibrutinib is currently being evaluated in several early phase clinical trials (NCT03939182, NCT03479268) [153]. A dual HDAC and PI3K inhibitor fimepinostat showed preclinical anti-lymphoma efficacy in MCL [154].