Loss of MYSM1 deubiquitinase catalytic activity protects against MYC-driven B cell lymphoma via tumor intrinsic effects and indirect modulation of antitumor immunity

Abstract

BackgroundMYC is an oncogenic transcription factor that is over-expressed, amplified, or otherwise dysregulated in over 50% of all cancers. This includes over 10% of diffuse large B-cell lymphomas (DLBCL), where MYC translocations are associated with a poor therapy response and inferior prognosis for the patients. However, because MYC lacks ligand-binding or catalytic domains, it is a highly challenging drug target, and there is a wide interest in novel approaches to inhibit MYC oncogenic functions. MYSM1 is a chromatin-binding deubiquitinase (DUB) that promotes gene expression by catalytically removing the histone H2AK119ub epigenetic mark. In recent work, we demonstrated that MYSM1 acts in cooperation with MYC to sustain the expression of oncogenic transcriptional programs in hematopoietic cells, identifying MYSM1 as a potential therapeutic target for MYC-driven malignancies. ResultsHere, we show for the first time that the loss of MYSM1 DUB catalytic activity, without the loss of MYSM1 protein expression, is sufficient to protect against MYC-driven lymphoma in murine models. We characterize the impact of MYSM1 loss-of-function on tumor cell physiology and on antitumor immunity, examining the tumor-intrinsic and the immune cell-mediated mechanisms involved in the protection against the disease. Leveraging human cancer genome databases, we provide first evidence linking MYSM1 loss-of-function to reduced fitness of human lymphoma cell lines in culture and to more favorable clinical outcomes in cancer patients. ConclusionsOverall, our studies support pharmacological inhibition of MYSM1 DUB catalytic function as a novel therapeutic strategy for MYC-driven lymphoma and potentially other cancers.