EZH2 mutation

The most used agents include hydroxyurea, interferon, hypomethylating agents, and JAK inhibitors, although none of them are disease-modifying. Allogeneic hematopoietic stem cell transplant remains the only potentially curative approach and should be considered in all eligible patients. Actionable mutations (CSF3R, NRAS/KRAS, and KIT) have also been identified, supporting the development of new agents targeting the involved pathways.

In terms of the immune microenvironment, the depleted lymphoma microenvironment (LME-DP) subtype, characterized by diminished immune cell infiltration, demonstrated a propensity for increased frequency in DHL/THL patients. Collectively, these findings advance the comprehensive understanding of DHL/THL pathobiology, underscoring the imperative for novel targeted agents and therapeutic approaches.

It is noteworthy that imatinib was more effective than dasatinib in our case, although the duration of remission was short. Our findings suggest that other therapies like allogeneic hematopoietic stem cell transplantation may need to be combined to improve long-term survival in ALL cases with BCR::PDGFRA.

Here we report a durable response in a patient with PBRM1 mutated cholangiocarcinoma treated with Tazemetostat. We provide hypothesis-generating mechanistic findings into the relationship between PBRM1 mutations and EZH2 inhibition and the interplay between the SWI/SNF and PRC2 complexes.

P1/2, N=58, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

These findings suggest that the STc of NN may be a precursor to poorly differentiated thyroid carcinoma arising from well-differentiated components through stepwise mutations. This case highlights the malignant potential of certain Noninvasive TFNDs and suggests the need for further analyses to clarify this hypothesis and reconsider their classification and management.

As a synergistic effect of BMI1 and EZH2 has already been demonstrated in other neoplasms, we hypothesize that acquiring an EZH2 mutation might be a crucial proliferation advantage in PICALM::MLLT10 positive cells. This may explain the high percentage of EZH2 mutated cases in this entity, but also supports the hypothesis of BMI1-mediated leukemogenesis.

Patients with myelodysplasia-related gene mutations (MRmut) and/or DNMT3A mutations experienced inferior outcomes after transplantation, requiring further exploration. Furthermore, similar prognoses among CR patients highlighted the need for monitoring specific molecular residual lesions.

Targeted therapies such as the EZH2 inhibitor tazemetostat have demonstrated efficacy in EZH2-mutant FL, while HDAC and BET inhibitors show variable responses across B cell malignancies. The limitations of current epigenetic therapies reflect the complexity of targeting epigenetic dysregulation rather than therapeutic futility. These challenges nonetheless highlight the relevance of epigenetic alterations as biomarkers and therapeutic targets, with potential to improve the management of mature B cell neoplasms.

A multicentre, randomised, phase 3 trial of tazemetostat combined with lenalidomide plus rituximab vs. lenalidomide plus rituximab in patients with R/R FL is ongoing (NCT04224493). HUTCHMED.

We identified a redistribution of histone 3 lysine 27 trimethylation at the GBP locus and showed that GBP2 overexpression impairs multilineage hematopoiesis by promoting apoptosis and skewing differentiation. These findings demonstrate that the oncogenic potential of Ezh2 Y641F is highly dependent on the cellular environment in which it is expressed and that the timing of mutation acquisition critically shapes the impact of EZH2 on hematopoiesis and disease outcome.

MPN transformation involves complex clonal evolution, with frequent clonal hematopoiesis-related mutations preceding driver mutations, preserved CALR, acquisition of TP53, RUNX1 and signaling mutations, and JAK2-V617F loss linked to poorer survival during BP transformation, which may influence therapeutic decisions.