The Histone Modifier KANSL2 Is an Actionable Biomarker in Multiple Myeloma

Epigenetic aberrations are key drivers of multiple myeloma, yet targeted therapies exploiting epigenetic alterations have not been established. By integrating clinical and molecular datasets of patients with multiple myeloma with an unbiased genetic in vivo screen, we identified KAT8 regulatory NSL complex subunit 2 (KANSL2) as a histone posttranslational modification-associated candidate oncogene. High expression of KANSL2 was associated with adverse prognosis in patients with multiple myeloma. Genetic gain- and loss-of-function models identified a protective role of KANSL2 toward 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 samples from patients with relapsed/refractory multiple myeloma confirmed that high KANSL2 expression is associated with selective multiple myeloma 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.