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| Item Type: | Article |
|---|---|
| Title: | The histone modifier KANSL2 is an actionable biomarker in multiple myeloma |
| Creators Name: | Jiang, Kaiting, Kirchner, Marieluise, Herzberg, Frederik, Zhao, Yan, Gasper, Amelie, Baumgartner, Francis, Jung, Paul, Braune, Jan, Schulze, Veronika, Isaakidis, Konstandina, Mertins, Philipp, Krönke, Jan, Wirth, Matthias, Keller, Ulrich and Habringer, Stefan |
| Abstract: | Epigenetic aberrations are key drivers of multiple myeloma (MM), yet targeted therapies exploiting epigenetic alterations have not been established. By integrating clinical and molecular MM patient data sets with an unbiased genetic in vivo screen, we identified KAT8 regulatory NSL complex subunit 2 (KANSL2) as a histone posttranslational modification (PTM)-associated candidate oncogene. High expression of KANSL2 was associated with adverse prognosis in MM patients. Genetic gain and loss of function models identified a protective role of KANSL2 towards genotoxic stress. By transcriptomics, proteomics and quantitative acetylome profiling, we identified a KANSL2-dependent specific molecular program targetable by acetylation-related modifiers. High KANSL2 levels increased sensitivity to the histone deacetylase (HDAC) inhibitor panobinostat and bromodomain and extra-terminal motif (BET) inhibitor OTX-015 and their combination. Ex vivo drug response profiling in relapsed/refractory MM patient samples confirmed that high KANSL2 expression is associated with selective MM cell killing by HDAC and BET inhibitors. Collectively, these findings position KANSL2 as a mediator of chemotherapy resistance and actionable biomarker for response to drugs targeting its epigenetic program. |
| Source: | Molecular Cancer Therapeutics |
| ISSN: | 1535-7163 |
| Publisher: | American Association for Cancer Research |
| Date: | 26 November 2025 |
| Official Publication: | https://doi.org/10.1158/1535-7163.mct-25-0379 |
| PubMed: | View item in PubMed |
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