Lack of smarcb1 expression characterizes a subset of peripheral t‐cell lymphomas enriched in children and young adults

Introduction: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Because patients respond poorly to current treatment regimens, identification of new therapeutic strategies is required. In a mouse tumor model, conditional deletion of Smarcb1 encoding a member of the SWI/SNF chromatin remodeling complex causes the majority of mice to develop mature T-cell lymphomas. The human counterpart, SMARCB1, is a bona fide tumor suppressor gene associated with the development of for example, rhabdoid tumors and schwannomas, but has also been shown to be involved in lymphocyte development. Methods: SMARCB1 (INI1) gene and protein expression was assessed in 315 patients with diverse mature T cell lymphomas by array-based mRNA profiling, immunohistochemistry and/or Western Blot. The DNA methylome was analyzed in SMARCB1-negative pediatric PTCL-NOS patients (n = 5) and murine T cell lymphomas of the Cd4-cre::Smarcb1fl/fl model (n = 5) using the Infinium MethylationEPIC and Mouse Methylation BeadChip, respectively. Murine Smarcb1-deficient T-cell lymphomas were further studied using droplet-based single cell RNA sequencing (Chromium, 10X Genomics). Results: SMARCB1 expression was heterogeneous between and within the 315 different human mature T-cell lymphoma entities. Loss of SMARCB1 expression in PTCL-NOS patients correlated with young age (Wald test, p value = 0.011). Molecular characterization and DNA methylation analysis revealed that loss of SMARCB1 expression in human PTCL largely occurs via somatic mutation and/or epigenetic silencing, whereas in contrast to rhabdoid tumors, germline SMARCB1 mutations were not observed. Comparison of the DNA methylome of human and murine PTCL-NOSSmarcb1- showed similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Increase of myeloid cell populations was confirmed in murine tumors by scRNA-seq analyses, which further revealed an immunosuppressive and pro-inflammatory tumor microenvironment (TME). Treatment of tumor-bearing mice with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversion of the exhaustion phenotype. Conclusions: Here we describe SMARCB1-negative PTCL-NOS as a potential new molecular subtype of PTCL-NOS significantly enriched in young patients. A strong concordance between naturally occurring SMARCB1-deficient PTCL in humans and in the targeted mouse model were found regarding epigenetic features. Our results provide a rationale for further investigation of potential HDACi combination therapies in SMARCB1-negative PTCL-NOS. Keywords: aggressive T-cell non-Hodgkin lymphoma, genomics, epigenomics, and other-omics No conflicts of interests pertinent to the abstract.