Single cell omics in the study of b cell lymphoma

Analysis of the genomic and transcriptomic landscape of tumors has contributed extensively to dissect the mechanisms of malignant transformation and to stratify patients based on genetic and molecular features. In the context of germinal center (GC)-derived B cell lymphomas, these studies have identified key genetic and epigenetic drivers of malignant transformation and informed on disease heterogeneity. In particular, transcriptomic studies led to the identification of the prognostically distinct GCB and ABC subtypes of diffuse large B cell lymphomas (DLBCL), that are now recognized by the WHO classification. In addition, extensive genetic characterization has pinpointed to the major players in the pathogenesis of DLBCL subtypes and more recently led to the development of genetic classifiers. Nonetheless, tumor heterogeneity is not only a feature observed across individual patients, rather a characteristic of each tumor itself. The genetic spectrum of intra-tumor heterogeneity has been long appreciated and inferred, for example, from the variant-allele frequencies of somatic mutations identified in bulk sequencing studies. Single-cell (sc)-transcriptomic technologies have provided the tools to dissect the heterogeneity of both tumor cells and normal infiltrating components. Several studies have explored follicular lymphoma and DLBCL by sc-transcriptomic analysis, highlighting the presence of diverse subpopulations and the contribution of the normal infiltrating cells to the tumor development and response to therapy. Recently, we have investigated Burkitt lymphoma (BL), the most common pediatric GC-derived lymphoma, using sc-transcriptomic and immunoglobulin repertoire analysis. The transcriptomic analysis restricted to the tumor cells showed, as expected, patient-specific features. Nonetheless, the large majority of specimens were characterized by the presence of distinct subpopulations that were recurrently detected across patients. This intra-tumor transcriptional heterogeneity was associated with multiple distinct features including cell cycle, activation markers and cell-of-origin signatures. Overall, we identified transcriptional intra-tumor heterogeneity that is retained across BL patients suggesting the presence of distinct programs in BL cells. Keywords: genomics, epigenomics, and other -omics, microenvironment, tumor biology and heterogeneity No conflicts of interests pertinent to the abstract.