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The histone modifier KANSL2 is an actionable biomarker in multiple myeloma

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 inhibitor panobinostat and bromodomain and extra-terminal motif inhibitor OTX-015 and their combination. Collectively, we identified KANSL2 to mediate chemotherapy resistance that could be overcome by targeting epigenetic regulators.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302047 | GEO | 2026/06/10

REPOSITORIES: GEO

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The histone modifier KANSL2 is an actionable biomarker for response to epigenetic modifiers in multiple myeloma

Project description: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 vivoscreen, 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 revealed that high KANSL2 expression enhances sensitivity to HDAC and BET inhibitors in primary MM patient samples. Collectively, these findings position KANSL2 as a mediator of chemotherapy resistance and actionable biomarker for response to epigenetic regulators.

2026-02-22 | PXD066205 | Pride

The NSL complex subunit KANSL2 regulates cell stemness and tumorigenesis in glioblastoma

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Role of different epigenetic drugs in reshaping murine melanoma tumor microenvironment

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Regulation of the NSL complex by TAF4A is critical for genome stability and quiescence of skeletal muscle stem cells

Project description:Acetylation of lamin A/C by the NSL complex, containing MOF and KANSL2, is instrumental for maintaining nuclear architecture and genome stability, but the mechanisms controlling expression of NSL complex components in different cell types are poorly characterized. Here, we describe that TAF4A, primarily known as a subunit of the general transcription factor TFIID, is critical for cell type-specific regulation of Kansl2 in MuSCs. Inactivation of Taf4a in MuSCs reduces expression of Kansl2 and alters post-translational modification of lamin A/C, thereby decreasing the stiffness of MuSC nuclei and disrupting the nuclear architecture. Using CUT&RUN technique, we found that TAF4A together with the heterotrimeric transcription factor NF-Y controls Kansl2 expression. In addition to destabilization of the nuclear architecture, reduced expression of Kansl2 in Taf4a-mutant MuSCs changes expression of numerous genes involved in chromatin regulation. The subsequent loss of heterochromatin and MuSC activation, in combination with pronounced genomic instability, activates MuSCs and impairs MuSC proliferation, which depletes the stem cell pool and abolishes skeletal muscle regeneration. We conclude that TAF4A-NF-Y-dependent transcription regulation safeguards heterochromatin and genome stability of MuSCs via the NSL complex.

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