Divergent Effects of EZH1 and EZH2 Protein Expression on the Prognosis of Patients with T-Cell Lymphomas

Schümann, Franziska Lea; Groß, Elisabeth; Bauer, Marcus; Rohde, Christian; Sandmann, Sarah; Terziev, Denis; Müller, Lutz; Posern, Guido; Wienke, Andreas; Fend, Falko; Hansmann, Martin‐Leo; Klapper, Wolfram; Rosenwald, Andreas; Harald, Stein; Dugas, Martin; Müller‐Tidow, Carsten; Wickenhauser, Claudia; Binder, Mascha; Weber, Thomas

doi:10.3390/biomedicines9121842

Cited by 11 publications

(11 citation statements)

References 39 publications

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“…This hypothesis is supported by data from epithelial tumors: in a large cohort of breast cancers, although subtype-dependent overexpression of EZH2 and H3K27m3 overexpression were found, not a single EZH2 mutation could be detected [ 17 ]. Furthermore, in a recent study on T cell lymphomas, again, no correlation between the immunohistochemical expression of H3K27m3/EZH2 and molecular alterations in the EZH2 gene could be identified [ 18 ]. Whether assessing tri-methylation of H3K27 might help to estimate the therapeutic effect of EZH2 - inhibitors remains to be addressed.…”

Section: Discussionmentioning

confidence: 99%

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H3K27m3 overexpression as a new, BCL2 independent diagnostic tool in follicular and cutaneous follicle center lymphomas

et al. 2022

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Approximately 15% of follicular lymphomas (FL) lack overexpression of BCL2 and the underlying translocation t(14;18). These cases can be diagnostically challenging, especially regarding follicular hyperplasia (FH). In a subset of FL, mutations in genes encoding for epigenetic modifiers, such as the histone-lysine N-methyltransferase EZH2 (enhancer of zeste homolog 2), were found, which might be used diagnostically. These molecular alterations can lead to an increased tri-methylation of histone H3 at position lysine 27 (H3K27m3) that, in turn, can be visualized immunohistochemically. The aim of this study was to analyze the expression of H3K27m3 in FL, primary cutaneous follicle center lymphomas (PCFCL), and pediatric-type FL (PTFL) in order to investigate its value in the differential diagnosis to FH and other B cell lymphomas and to correlate it to BCL2 expression and the presence of t(14;18). Additionally, the mutational profile of selected cases was considered to address H3K27m3’s potential use as a surrogate parameter for mutations in genes encoding for epigenetic modifiers. Eighty-nine percent of FL and 100% of PCFCL cases overexpressed H3K27m3, independently of BCL2, EZH2, and the presence of mutations. In contrast, 95% of FH and 100% of PTFL cases lacked H3K27m3 overexpression. Other B cell lymphomas considered for differential diagnosis also showed overexpression of H3K27m3 in the majority of cases. In summary, overexpression of H3K27m3 can serve as a new, BCL2 independent marker in the differential diagnosis of FL and PCFCL, but not PTFL, to FH, while being not of help in the differential diagnosis of FL to other B cell lymphomas.

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Section: Discussionmentioning

confidence: 99%

“…So far, contradictory results are available concerning H3K27m3’s or EZH2’s use as surrogate markers [ 17 , 18 ], with a single study confirming H3K27m3’s feasibility in FL [ 9 ]. Further on, H3K27m3 expression has never been used for diagnostic purposes in the differential diagnosis of FL to FH and other B cell lymphomas.…”

Section: Introductionmentioning

confidence: 99%

H3K27m3 overexpression as a new, BCL2 independent diagnostic tool in follicular and cutaneous follicle center lymphomas

et al. 2022

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“…As we and others have shown before, T-cell lymphomas overexpress EZH2, which is correlated to worse survival rates [11,12]. This gives a rationale to evaluate EZH2 inhibition as a potential new therapy of T-cell lymphomas, as a single agent but also in combination with cytotoxic agents, which is currently discussed [13].…”

Section: Introductionmentioning

confidence: 88%

SAM-Competitive EZH2-Inhibitors Induce Platinum Resistance by EZH2-Independent Induction of ABC-Transporters

Groß

Hilger²,

Schümann

et al. 2023

Cancers

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T-cell lymphomas are heterogeneous and rare lymphatic malignancies with unfavorable prognosis. Consequently, new therapeutic strategies are needed. The enhancer of zeste homologue 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 and responsible for lysine 27 trimethylation of histone 3. EZH2 is overexpressed in several tumor entities including T-cell neoplasms leading to epigenetic and consecutive oncogenic dysregulation. Thus, pharmacological EZH2 inhibition is a promising target and its clinical evaluation in T-cell lymphomas shows favorable results. We have investigated EZH2 expression in two cohorts of T-cell lymphomas by mRNA-profiling and immunohistochemistry, both revealing overexpression to have a negative impact on patients’ prognosis. Furthermore, we have evaluated EZH2 inhibition in a panel of leukemia and lymphoma cell lines with a focus on T-cell lymphomas characterized for canonical EZH2 signaling components. The cell lines were treated with the inhibitors GSK126 or EPZ6438 that inhibit EZH2 specifically by competitive binding at the S-adenosylmethionine (SAM) binding site in combination with the common second-line chemotherapeutic oxaliplatin. The change in cytotoxic effects under pharmacological EZH2 inhibition was evaluated revealing a drastic increase in oxaliplatin resistance after 72 h and longer periods of combinational incubation. This outcome was independent of cell type but associated to reduced intracellular platinum. Pharmacological EZH2 inhibition revealed increased expression in SRE binding proteins, SREBP1/2 and ATP binding cassette subfamily G transporters ABCG1/2. The latter are associated with chemotherapy resistance due to increased platinum efflux. Knockdown experiments revealed that this was independent of the EZH2 functional state. The EZH2 inhibition effect on oxaliplatin resistance and efflux was reduced by additional inhibition of the regulated target proteins. In conclusion, pharmacological EZH2 inhibition is not suitable in combination with the common chemotherapeutic oxaliplatin in T-cell lymphomas revealing an EZH2-independent off-target effect.

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“…A univariable analysis has reported that high EZH2 and H3K27me3 expression are associated with poor overall survival (OS) and progression-free survival (PFS) in patients with T-cell lymphomas [37]. ATL, a T-cell lymphoma with extremely poor prognostic, has an excessive H3K27me3 accumulation [18,38].…”

Section: Emerging Therapies Targeting H3k27me3 Abnormalitiesmentioning

confidence: 99%

“…This could be attributed to the higher activity and plasticity of EZH2, although the details remain unknown. A univariable analysis has reported that high EZH2 and H3K27me3 expression are associated with poor overall survival (OS) and progression-free survival (PFS) in patients with T-cell lymphomas [ 37 ].…”

Section: Emerging Therapies Targeting H3k27me3 Abnormalitiesmentioning

confidence: 99%

The role of epigenetics in T-cell lymphoma

Yamagishi

2022

Int J Hematol

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Malignant lymphomas are a group of diseases with epigenomic abnormalities fundamental to pathogenesis and pathophysiology. They are characterized by a high frequency of abnormalities related to DNA methylation regulators (DNMT3A, TET2, IDH2, etc.) and histone modifiers (EZH2, HDAC, KMT2D/MLL2, CREBBP, EP300, etc.). These epigenomic abnormalities directly amplify malignant clones. They also originate from a hematopoietic stem cell-derived cell lineage triggered by epigenomic changes. These characteristics are linked to their high affinity for epigenomic therapies. Hematology has led disease epigenetics in the areas of basic research, clinical research, and drug discovery. However, epigenomic regulation is generally recognized as a complex system, and gaps exist between basic and clinical research. To provide an overview of the status and importance of epigenomic abnormalities in malignant lymphoma, this review first summarizes the concept and essential importance of the epigenome, then outlines the current status and future outlook of epigenomic abnormalities in malignant lymphomas.

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Divergent Effects of EZH1 and EZH2 Protein Expression on the Prognosis of Patients with T-Cell Lymphomas

Cited by 11 publications

References 39 publications

H3K27m3 overexpression as a new, BCL2 independent diagnostic tool in follicular and cutaneous follicle center lymphomas

H3K27m3 overexpression as a new, BCL2 independent diagnostic tool in follicular and cutaneous follicle center lymphomas

SAM-Competitive EZH2-Inhibitors Induce Platinum Resistance by EZH2-Independent Induction of ABC-Transporters

The role of epigenetics in T-cell lymphoma

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