Atypical Teratoid / Rhabdoid Tumors – AT/RT
David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack in Brain and Spinal Tumors of Childhood, 2020
Epigenetic targeting is currently one of the most active areas of research in drug development. The inhibition of enzymatic activities involved in epigenetic silencing by histone deacetylases (HDACs), DNA methyltransferases (DNMTs), and enhancer of zeste homolog 2 (EZH2) is being tested in multiple active clinical trials. The antagonistic relationship between SWI/SNF and the polycomb repressive complex 2 (PRC2) plays a critical role in gene transcription and makes it an attractive target for therapy in AT/RT.114 EZH2 is critical for normal development and lineage-specific differentiation. Overexpression of EZH2 leads to the maintenance of a pluripotent state.115 Preclinical studies reported elevated expression of EZH2 in SMARCB1-deficient cells and demonstrated apoptosis in EZH2-depleted rhabdoid tumor cell lines.116 Further experimentation demonstrated upregulation of EZH2 following SMARCB1 loss. This was accompanied by widespread trimethylation of histone H3K27 and repression of p16INK4.117 Potent, selective EZH2 inhibitors have been developed. One of these, tazemetostat (EPZ-6438), is a selective orally bioavailable inhibitor of EZH2’s enzymatic activity.
Weaver Syndrome
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Located on chromosome 7q36.1, the enhancer of zeste, drosophila, homolog 2 gene (EZH2) comprises multiple alternative transcripts, the longest of which has 20 exons and encodes a 751-amino-acid histone methyltransferase (EZH2) with a critical SET [su(var)3–9, enhancer of zeste, trithorax] domain, a pre-SET CXC domain, and two additional SANT (Sw13, Ada2, N-cor TFIIIB) domains. EZH2 constitutes the catalytic subunit of the polycomb-repressive complex 2 (PRC2), which also includes additional core components SUZ12 (suppressor of zeste 12) and EED (embryonic ectoderm development). As a highly conserved epigenetic modifying complex, PRC2 induces trimethylation of histone H3 at lysine 27 (resulting in H3K27me3), which serves as an epigenetic signal for chromatin condensation and transcriptional repression and contributes to the regulation of chondrocyte proliferation and hypertrophy in the growth plate [9]. Functional loss of any of the components (i.e., EZH2, SUZ12, and EED) compromises the enzymatic activity of PRC2 and subsequent reduction of H3K27me3, leading to transcriptional activation of loci to which H3K27me3 is bound [10–12].
Myelodysplastic Syndromes
Wojciech Gorczyca in Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
Mutations in RUNX1, TP53, and NRAS are most strongly associated with severe thrombocytopenia and an increased proportion of BM blasts. The presence of mutations in five genes, TP53, EZH2, ETV6, RUNX1, and ASXL1, is associated with poor prognosis [11,83]. Mutations in one or more of these genes are present in 31% of patients. Most patients with EZH2 and ASXL1 mutations have low or intermediate-1 risk based on the IPSS. The presence of EZH2 mutations is strongly associated with decreased overall survival. TP53 mutations are observed mostly in patients with intermediate-2 or high risk according to the IPSS and are strongly associated with thrombocytopenia, elevated blasts, and complex karyotype. TET2 mutations are associated with good prognosis.
New directions in treating peripheral T-cell lymphomas (PTCL): leveraging epigenetic modifiers alone and in combination
Published in Expert Review of Hematology, 2019
Helen Ma, Owen A. O’Connor, Enrica Marchi
Another novel target is the enhancer of zeste homolog 2 (EZH2). EZH2 is the enzymatic subunit of polycomb repressor complex 2 involved with histone acetylation and subsequent epigenetic gene suppression [94]. EZH2 has been found to be expressed in many types of PTCL, including ALCL (ALK-positive and -negative as well as primary cutaneous subtypes), PTCL-NOS, AITL, NKTL, and ATLL by immunohistochemistry [42,95]. ATLL is related to human T-lymphotropic virus type 1 (HTLV-1) infection, though only a minority of patients infected progress to having lymphoma. Viral proteins such as Tax, Rex, p30, and HBZ are associated with the pathogenesis of lymphoma. EZH2 has been found to be necessary for Tax-dependent cell growth and immortalization [96]. Lymphocyte activation by anti-CD3/CD28 stimulation or polymethacrylate/ionomycin increases EZH2 expression. In ATLL, NF-kB activation plays a critical role in the chronic expression of EZH2. Targeting this pathway with EZH2 inhibitors may reverse the reprogramming and specifically eliminate cancerous cells while sparing normal CD4 + T-cells. Early phase clinical trials are ongoing to test this hypothesis [42,97,98].
Therapeutic potential of enhancer of zeste homolog 2 in autoimmune diseases
Published in Expert Opinion on Therapeutic Targets, 2019
Yue-Xin Yang, Hui-Hui Shen, Fan Cao, Liang-Yu Xie, Guang-Lin Zhu, Napoleon Bellua Sam, De-Guang Wang, Hai-Feng Pan
To date, expertise in epigenetics have convincingly demonstrated EZH2 as a pivotal and novel therapeutic target in malignancies, and postulated its potential role in triggering disease flares and aggravations of ADs [15,19,21–23]. Generally, EZH2 is a repressive epigenetic modifier that participates in histone, DNA, and cytosolic methylation. Its ultimate efficacy in governing chromatin accessibility and thus gene silencing is clarified in numerous transcriptional reprogramming processes including MMP-9, Jagged-1, IFR4, FRA2, FLI1, etc., and myriad cellular signaling pathways involving Wnt signaling, Akt signaling, NF-κB signaling, and insulin/IGF signaling. Experimental models of diseases and data collected from patients have revealed the therapeutic potential of targeting EZH2 in specific clinical settings, though paradoxical observations have never ceased to overturn our original views (Table 1).
Identifying prognostic gene panels in acute myeloid leukemia
Published in Expert Review of Hematology, 2023
Joaquin Sanchez-Garcia, Josefina Serrano, Esther Prados de La Torre, Juana Serrano-López, Clara Aparicio-Perez, E Barragán, Pau Montesinos
Additional sex combs-like 1 (ASXL1) gene is located at 20q11 encoding a chromatin-regulator, which is mutated in clonal hematopoiesis of indeterminate potential (CHIP) as well as in all myeloid malignancies including AML (in approximately 20% of cases) conferring adverse prognosis [101]. EZH2 is gene located at 7q36 encoding a histone methyltransferase component of the Polycomb group (PcG) of proteins acting as a transcriptional repressor [102]. BCOR gene located at Xp14 codes a protein interacting corepressor of BL6 and it has been reported to be rare but recurrently mutated in AML found in up to 15% of AML with normal karyotype conferring adverse prognosis [103]. STAG2 gene located at Xq25 encodes a subunit of the cohesion complex responsible for the separation of chromatids during mitoses. Mutations leading to loss of function are detected in AML (~5%) and MDS (~20%) [104] without clear impact on outcomes.
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