Targeting EZH2 for the treatment of hepatosplenic T-cell lymphoma

Pikman, Yana; Conway, Amy Saur; Robichaud, Amanda L.; Kitara, Samuel; Church, Alanna J.; Kennedy, Alyssa L.; Silverman, Lewis B.; Billett, Amy L.; Weinstock, David M.; Harris, Marian H.; Stegmaier, Kimberly

doi:10.1182/bloodadvances.2019001256

Cited by 5 publications

(2 citation statements)

References 17 publications

(17 reference statements)

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“…Pikman reported a PDX mouse model established with MNC from a patient with HSTCL carrying activating mutations in EZH2, as well as mutations in CUX1 and ASXL1 . Interestingly treatment of mice with tazemetostat reduced disease burden and significantly prolonged their survival in this aggressive mouse model [35 ▪▪ ].…”

Section: Discussionmentioning

confidence: 90%

Hepatosplenic T-cell lymphoma: treatment challenges

Bron

Leval

Michiels

et al. 2021

Current Opinion in Oncology

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Purpose of reviewHepatosplenic lymphoma (HSTCL) is a rare T-cell malignancy occurring in young males, associated with immune deficiency in 20% of the cases which, despite aggressive treatments, has a poor survival. Specific recommendations for first-line treatment remain debatable. Recent findingsPublished data covering case reports or series of HSTCL concur that allogeneic stem cell transplant should be proposed as a consolidation after response to chemotherapy in all patients eligible for transplant. In the light of two recent clinical examples, we also confirm that specific chemotherapy and a first-line consolidation with allogeneic transplantation when a donor is available to represent a treatment of choice these rare and distinctive lymphomas. Recent molecular studies are summarized in this review and suggest potential targets for new therapeutic strategies.

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Section: Discussionmentioning

confidence: 90%

Hepatosplenic T-cell lymphoma: treatment challenges

Bron

Leval

Michiels

et al. 2021

Current Opinion in Oncology

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“…Compared with solid tumors and B-cell lymphomas, targeting EZH2 in T-cell lymphomas is still in the early stages of investigation. In a preclinical study with a patient-derived xenograft model of hepatosplenic T-cell lymphoma (HSTL), treatment with tazemetostat significantly prolonged the survival of mice with this aggressive lymphoma [28]. In a recent phase 2 clinical trial (www.clinicaltrials.gov, NCT04102150, accessed on 30 January 2024), a dual EZH2 and EZH1 inhibitor, valemetostat, was used to treat patients with relapsed or refractory (R/R) ATLL.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Enhancer of Zeste Homolog 2 (EZH2) with Associated pERK Co-Expression and PRC2 Complex Protein SUZ12 Correlation in Adult T-Cell Leukemia/Lymphoma

Chai,

Choudhuri,

Gong

et al. 2024

Cancers

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EZH2, a subunit of the polycomb repressive complex 2 (PRC2), is an important methyltransferase that catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3). EZH2 is overexpressed in various malignancies. Here, we investigated EZH2 expression and potential signaling molecules that correlate with EZH2 expression in ATLL and other T-cell neoplasms. Immunohistochemical staining (IHC) was performed for EZH2, pERK, MYC, and pSTAT3 on 43 ATLL cases and 104 cases of other T-cell neoplasms. Further IHC studies were conducted for Ki-67, SUZ12, and H3K27me3 on ATLL cases. All ATLL cases showed EZH2 overexpression. In other T-cell neoplasms, a high prevalence of EZH2 overexpression was identified (86%), except for T-PLL (33%). In ATLL, EZH2 overexpression correlated with pERK co-expression (86%), while only a small subset of cases showed MYC (7%) or pSTAT3 (14%) co-expression. In the other T-cell neoplasms, there was a variable, but higher, co-expression of EZH2 with pERK, MYC, and pSTAT3. In ATLL, enhanced EZH2 expression correlated with higher Ki-67 staining, SUZ12 (another PRC2 subunit), and H3K27me3 co-expression. In conclusion, EZH2 is overexpressed in ATLL and is associated with pERK expression. It correlates with an increased proliferation index, indicating an aggressive clinical course. EZH2 also correlates with SUZ12 and H3K27me3 co-expression, suggesting its PRC2-dependent catalytic activity through trimethylation. Additionally, EZH2 is overexpressed in most T-cell neoplasms, suggesting that EZH2 could function as an oncogenic protein in T-cell tumorigenesis. EZH2 and pERK could serve as potential therapeutic targets for treating aggressive ATLL. EZH2 could also be targeted in other T-cell neoplasms.

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