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Familial Monosomy 7 Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
EZH2 (7q36.1)) encodes a methyltransferase participates in the formation of the polycomb repressive complex 2 (PRC2), binds to lysine 27 of histone H3 (H3K27) and catalyzes the trimethylation of H3K27. Mutations in the EZH2 gene eliminate its methyltransferase activity and are observed in 10% of MDS cases. In synergy with TET2 or RUNX1 mutations, EZH2 haploinsufficiency linked to monosomy 7/del(7q) contributes to MDS pathogenesis.
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
ATLL cells show diverse cytogenetic abnormalities, with the most frequent being gains at chromosomes 14q, 7q and 3p and losses at chromosomes 6q and 13q. The earliest genetic event appears to be epigenome alterations initiated by the HTLV-1 transcriptor of the X-gene region, Tax, through the EZH2 gene. There is then an accumulation of mutations affecting the TCR and NF-κB pathways (PLCG1, PRKCB, CARD11, VAV1 and IRF4), inactivation of tumour suppressors, such as p53, p15INK4A, p16INK4B and mutations in TET2 and MLL3, which are thought to be pivotal in disease development. Other frequently mutated genes are those implicated in cell-cycle genes (CDC2, cyclin B), tyrosine kinase signalling pathways (SYK, LYN), anti-apoptotic factors (BIRC5), calcium metabolism (RANKL, PTHLH), NRXN3, CCR4, CCR7, TSLC1, CAV1 and prostaglandin D2. It is also likely that ATLL cells also affect PD1 receptors and proteins involved in cellular adhesion, within the tumour microenvironment. ENKTL appears to have a unique molecular signature affecting PRDM1, BCOR, ATG5, AIM1 genes and the AURKA, NOTCH-1, NF-κB and JAK/STAT3 pathways.
Novel synthetic drugs for the treatment of non-Hodgkin lymphoma
Published in Expert Opinion on Pharmacotherapy, 2021
Farheen Manji, Robert Puckrin, Douglas A. Stewart
Mutations in the EZH2 gene, which encodes the epigenetic regulator enzyme ‘enhancer of zeste homolog 2ʹ, have been identified in 22–29% of patients with FL [107]. The oral EZH2 inhibitor tazemetostat is administered at 800 mg orally twice daily and should be avoided with moderate to strong CYP3A inducers and inhibitors [108]. In a phase II study of 99 patients with relapsed/refractory FL, tazemetostat achieved an ORR of 69% in EZH2-mutated FL and 35% in EZH2 wild-type FL with mDOR 10.9 and 13.0mo, respectively [109]. Adverse reactions include fatigue, cytopenias, infection, pain, and increased risk of secondary malignancies. Based on these results, tazemetostat was granted accelerated U.S. FDA approval for patients with EZH2-mutated FL after ≥2 prior systemic therapies, and for patients with relapsed/refractory FL with no satisfactory alternative treatment options [108]. The activity of tazemetostat is being explored in relapsed/refractory B-cell lymphomas in a number of early-phase studies (NCT03456726, NCT03009344, NCT01897571, NCT02220842).
Investigational drugs for the treatment of diffuse large B-cell lymphoma
Published in Expert Opinion on Investigational Drugs, 2021
Andrea Patriarca, Gianluca Gaidano
Epigenetic modulation of histones plays a critical role in oncogenic transformation in many malignancies and is an area of intense clinical research. The genes encoding chromatin-modifying proteins are frequently targeted by DNA mutations in B-cell NHL deriving from GC cells and including DLBCL [43,44]. The methyltransferase encoded by the EZH2 gene makes part of the PRC2 (for Polycomb Repressive Complex 2) complex and can methylate histone 3 lysine 27 (H3K27), generating the histone mark H3K27me3 that favors repression of transcription (Figure 1). In lymphoid development, EZH2 downregulates the expression of genes regulating cell cycle and differentiation and is counteracted by the SWI/SNF (Switch/Sucrose NonFermentable) multiprotein complex that also participates in chromatine remodeling [45,46]. Gain of function mutations of EZH2 are reported in 20% of GC B cell lymphoma, resulting in an aberrant proliferative dependency on EZH2 activity and disruption of the differentiation process through hyper-trimethylation of H3K27 [43–46].
Sequencing the next generation of glioblastomas
Published in Critical Reviews in Clinical Laboratory Sciences, 2018
In addition to their role in cellular differentiation and proliferation, non-coding (nc)RNA, including micro (mi)RNA, and long non-coding (lnc)RNA, have oncogenic and tumor suppressive functions in different cancers [106]. miRNAs regulate gene expression post-transcriptionally by binding to mRNA and suppressing translation [109]. Abnormal expression of miRNA can induce either tumor suppression or tumor formation. Two examples are miR-9/9*, the inhibition of which leads to reduced neurosphere formation in CD133 + cells, and miR-17–92, the inhibition of which causes decreased cell proliferation and apoptosis of glioblastoma stem cells. In addition, miR-124 and miR-137, which are up-regulated during adult stem cell neural differentiation, are down-regulated, together with the miR-128 tumor suppressor, in glioblastomas [108]. While miR-21 is the only miRNA that shows consistent up-regulation in glioblastomas, down-regulation of miR-132 is observed in 60% of the reported analyses [106,109]. Also, histone modifications, especially trimethylation of histone H3 lysine 27 (H3K27me3), are found in glioblastomas. Production of di- and tri-methylated histone H3 (H3K27me2 and H3K27me3) is a result of the activity of the catalytic subunit EZH2 of PRC2, which has histone methyltransferase activity and specificity for H3K27. The EZH2 gene has been found to be up-regulated in glioblastoma samples [110,111]. It has been shown recently that K27M or G34R/G34V mutations in H3F3A are present in glioblastoma [108]. The H3F3A G34 mutation is accompanied by mutations in TP53, ATRX and DAXX, DNA hypomethylation, and hemispheric location, while the H3F3A K27 mutation is associated with mutations in TP53, DNA hypomethylation, midline location and poor outcome.