Dr. Anastasia Nijnik

Canada

Loss of MYSM1 deubiquitinase catalytic activity protects against MYC-driven lymphoma

Dania Shaban 1,2,#, Viktoria Plackoska 1,2,#, Yue Liang 1,2, Nay Najm 1,2, Francis Robert 3,4, Sidong Huang 3,4,5, Anastasia Nijnik 1,2*

1 Department of Physiology, McGill University, Montreal, QC, Canada
2 McGill University Research Centre on Complex Traits, McGill University, QC, Canada
3 Department of Biochemistry, McGill University, Montreal, QC, Canada
4 Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC, Canada
5 Department of Human Genetics, McGill University, Montreal, Canada.

# contributed equally to this work

Abstract

Background

MYC 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.

Methods

The current study utilizes transgenic murine models of MYC-driven B cell lymphoma to comprehensively analyze the role of MYSM1 in tumor cell physiology and in antitumor immunity. This encompasses mouse survival studies, followed by genomic analyses, flow cytometry, and functional characterization with tumor cells and the different tumor infiltrating immune cell lineages. Furthermore, using public cancer genome databases we assess the association between MYSM1 locus genomic aberrations and cancer prognosis in human.

Results

We demonstrate 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 the 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.

Conclusions

Overall, our studies support pharmacological inhibition of MYSM1 DUB catalytic function as a novel therapeutic strategy for MYC-driven lymphoma and potentially other cancers.