ArticleBiomarker research2023
SETD2 non genomic loss of function in advanced systemic mastocytosis is mediated by an Aurora kinase A/MDM2 axis and can be therapeutically targeted.
Article in Biomarker research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 6 citations in OpenAlex.
- Epigenetic alterations in Myeloid Malignancies.Advances in experimental medicine and biology · 2026Review
- Emerging role of SETD2 in the development and function of immune cells.Genes & diseases · 2025Review
- Next Generation Sequencing of Genes With Epigenetic Alterations in Mastocytosis.Clinical and translational allergy · 2025Article
- Building a Therapeutic Bridge Between Dogs and Humans: A Review of Potential Cross-Species Osteosarcoma Biomarkers.International journal of molecular sciences · 2025Review
- SETD2 loss of function is a recurrent event in advanced-phase chronic myeloid leukemia and contributes to genomic instability: SETD2 loss in Chronic Myeloid Leukemia.Clinical and translational medicine · 2025Article
- [Mastocytosis-a frequently unrecognized disease].Dermatologie (Heidelberg, Germany) · 2024Article
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Authors and funding
16 authors at 10 institutions in 3 countries.
Funding
Abstract
backgroundThe SETD2 tumor suppressor gene encodes a histone methyltransferase that safeguards transcription fidelity and genomic integrity via trimethylation of histone H3 lysine 36 (H3K36Me3). SETD2 loss of function has been observed in solid and hematologic malignancies. We have recently reported that most patients with advanced systemic mastocytosis (AdvSM) and some with indolent or smoldering SM display H3K36Me3 deficiency as a result of a reversible loss of SETD2 due to reduced protein stability.
methodsExperiments were conducted in SETD2-proficient (ROSA
resultsHere, we show that the proteasome inhibitors suppress cell growth and induce apoptosis in neoplastic mast cells by promoting SETD2/H3K36Me3 re-expression. Moreover, we found that Aurora kinase A and MDM2 are implicated in SETD2 loss of function in AdvSM. In line with this observation, direct or indirect targeting of Aurora kinase A with alisertib or volasertib induced reduction of clonogenic potential and apoptosis in human mast cell lines and primary neoplastic cells from patients with AdvSM. Efficacy of Aurora A or proteasome inhibitors was comparable to that of the KIT inhibitor avapritinib. Moreover, combination of alisertib (Aurora A inhibitor) or bortezomib (proteasome inhibitor) with avapritinib allowed to use lower doses of each drug to achieve comparable cytotoxic effects.
conclusionsOur mechanistic insights into SETD2 non-genomic loss of function in AdvSM highlight the potential value of novel therapeutic targets and agents for the treatment of patients who fail or do not tolerate midostaurin or avapritinib.
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