Characterization of the genome and tumor microenvironment of human B-cell lymphoma

Non-Hodgkin lymphoma (NHL) is the 13th most common type of cancer worldwide in 2020 and consists mainly of human B-cell lymphoma (approximately 85%). Diffuse large B-cell lymphoma (DLBCL) is the most common NHL subtype (approximately 30%). Several factors have been suggested to be associated with DLBCL lymphomagenesis and unfavorable outcomes, including cell of origin, viral infection, aberrant activation-induced cytidine deaminase (AID) activity, tumor microenvironment (TME) pattern, and immunodeficiency. In the last decade, high-throughput next-generation sequencing (NGS) has made it possible to study genetic variations and transcription genome-wide. Using NGS on the genomes and transcriptomes of DLBCL at the bulk tissue or single-cell level, we investigated the associations between these factors and DLBCL.

In study I, we explored the associations between HBV infection (surface antigen positive, HBsAg+) and DLBCL. We observed increased mutagenesis rates and different sets of mutated genes in HBsAg+ DLBCL genomes, which were associated with APOBEC and AID activities. We found that highly expressed genes in HBsAg+ DLBCL were enriched with genes regulated by BCL6, FOXO1, and ZFP36L1. Our data suggest that HBV-associated DLBCL can be considered as a distinct subtype. In study II, we identified seven genomic mutational signatures in DLBCL and follicular lymphoma (FL), including a novel signature related to aberrant somatic hypermutation (SHM). For the localized clustered mutations (kataegis), we characterized two major mutational signatures (K1 and K2), which resulted from AID and DNA polymerase η activities, respectively. K1 was related to mutations/translocations in the immunoglobulin (Ig) switch region and the ABC subtype of DLBCL. In contrast, K2 was associated with mutations in the Ig variable region and the GCB subtype of DLBCL and FL. Our data suggested that mutations associated with aberrant AID activity could be related to distinct developmental paths for the two major cell-of-origin subtypes of B-cell lymphoma. In study III, we studied malignant and infiltrating immune cells in DLBCL at the single-cell level. We revealed high intra- and intertumor heterogeneity and showed that activated MAPK signaling is associated with the relapse of DLBCL. We have also identified a dynamic TME in DLBCL, which may further contribute to disease heterogeneity. Furthermore, we discovered unique features in HBsAg+ DLBCL, with a higher expression level of major histocompatibility complex class II genes in malignant cells, stronger CD40-mediated interaction between malignant cells and CD4+ T cells, and a more immunosuppressive TME. In study IV, we performed an in-depth analysis of lymphoma genomes derived from inborn errors of immunity (IEI). We identified a novel mutation target, BRWD3, that is highly mutated in a subgroup of activated p110δ syndrome patients. We characterized five genomic mutational signatures in IEI-associated lymphomas, including two DNA repair deficiency-related signatures.

In conclusion, we presented comprehensive genomic and transcriptomic studies that may help to understand the complex mechanism underlying B cell lymphomagenesis. The genetic alterations and gene expression profiles identified in these studies pave the way for the development of novel therapeutic strategies for lymphoma patients.

List of scientific papers

I. Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma. Ren W*, Ye X*, Su H*, Li W*, Liu D, Pirmoradian M, Wang X, Zhang B, Zhang Q, Chen L, Nie M, Liu Y, Meng B, Huang H, Jiang W, Zeng Y, Li W, Wu K, Hou Y, Wiman KG, Li Z, Zhang H, Peng R, Zhu S, Pan-Hammarström Q. Blood. 2018 Jun 14;131(24):2670-2681. *Shared first authors.
https://doi.org/10.1182/blood-2018-12-894097

II. Genome-wide mutational signatures revealed distinct developmental paths for human B cell lymphomas. Ye X*, Ren W*, Liu D, Li X, Li W, Wang X, Meng FL, Yeap LS, Hou Y, Zhu S, Casellas R, Zhang H, Wu K, Pan-Hammarström Q. J Exp Med. 2021 Feb 1;218(2):e20200573. *Shared first author.
https://doi.org/10.1084/jem.20200573

III. A single-cell atlas of tumor and infiltrating immune cells in human B-cell lymphoma. Ye X*, Wang L*, Nie M*, Wang Y, Dong S, Li G, Li Z, Wu K, Pan-Hammarström Q. *Shared first authors. [Submitted]

IV. Genetic basis of B-cell lymphomagenesis in patients with inborn errors of immunity. Ye X*, Maglione PJ*, Wehr C*, Deripapa E, Liu D, Li X, Du L, Giannoula Y, Borte S, Abolhassani H, Ko HB, Hou Y, Zhu S, Wu K, Sander B, Grimbacher B, Hammarström L, Rosenzweig S, Fedorova A, Shcherbina A, Warnatz K, Cunningham-Rundles C, Pan-Hammarström Q. *Shared first authors. [Manuscript]