SETD2 is a novel and druggable dependency in IMiD/CELMoD resistant multiple myeloma models
SETD2 is a histone methyltransferase and is the only enzyme known to be capable of trimethylation of histone 3 lysine 36 (H3K36me2 → H3K36me3). SETD2 can also methylate non-histone proteins and is important in transcriptional regulation, RNA splicing, DNA damage repair and B cell development and differentiation [ 1 , 2 ]. SETD2 inhibition has been shown to reduce the proliferation of Multiple Myeloma (MM) and Diffuse Large B-cell Lymphoma (DLBCL) cell lines and reduce tumour burden in cell line-derived xenograft models [ 1 ]. The SETD2 inhibitor EZM0414 was initially granted fast-track FDA designation and investigated in a phase 1 clinical trial in patients with relapsed/refractory MM and DLBCL (NCT05121103), but this study terminated early due to business decisions.
Authors
- Sarah Anne Bird (ORCID: https://orcid.org/0000-0001-8080-0937)
- Marco P. Licciardello (ORCID: https://orcid.org/0000-0003-3197-4855)
- Paul Andrew Clarke (ORCID: https://orcid.org/0000-0001-9342-1290)
- Brian A. Walker (ORCID: https://orcid.org/0000-0002-8615-6254)
- Yigen Li (ORCID: https://orcid.org/0000-0002-0420-214X)
- Yakinthi Chrisochoidou (ORCID: https://orcid.org/0009-0002-2831-1321)
- Fernando J. Sialana (ORCID: https://orcid.org/0000-0001-9083-1657)
- Enze Liu (ORCID: https://orcid.org/0000-0003-3162-461X)
- Shannon Martin
- Jack Cheung
- Charlotte Pawlyn (ORCID: https://orcid.org/0000-0002-7190-0028)
- Salomon Morales
- Mara Mandelia
- Amy Wilson
- James Smith
Institutions
- Royal Marsden NHS Foundation Trust (GB)
- Institute of Cancer Research (GB)
- University of Miami (US)
- Royal Marsden Hospital (GB)
Publication Details
- Journal
- Blood Cancer Journal
- Published
- 2026-10-06
- DOI
- https://doi.org/10.1038/s41408-026-01632-6
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00