Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice

• Published in: Blood 2021-04, Vol.137 (13), p.1741-1753
• Main Authors: Raboso-Gallego, Javier, Casado-García, Ana, Jiang, Xiaoyu, Isidro-Hernández, Marta, Gentles, Andrew J., Zhao, Shuchun, Natkunam, Yaso, Blanco, Oscar, Domínguez, Verónica, Pintado, Belén, Alonso-López, Diego, De Las Rivas, Javier, Vicente-Dueñas, Carolina, Lossos, Izidore S., Sanchez-Garcia, Isidro
• Format: Article
• Language: English
• Subjects: Animals; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell Line; Female; Gain of Function Mutation; Gene Expression Regulation, Neoplastic; Germinal Center - metabolism; Germinal Center - pathology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Intracellular Signaling Peptides and Proteins - genetics; Lymphoid Neoplasia; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Mice; Mice, Inbred C57BL; Microfilament Proteins - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2020004996

Diffuse large B-cell lymphomas (DLBCLs) are clinically and genetically heterogeneous tumors. Deregulation of diverse biological processes specific to B cells, such as B-cell receptor (BCR) signaling and motility regulation, contribute to lymphomagenesis. Human germinal center associated lymphoma (HGAL) is a B-cell–specific adaptor protein controlling BCR signaling and B lymphocyte motility. In normal B cells, it is expressed in germinal center (GC) B lymphocytes and promptly downregulated upon further differentiation. The majority of DLBCL tumors, primarily GC B-cell types, but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express human HGAL at different stages of hematopoietic development using 3 restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells, pro-B cells, or GC B cells. Following immune stimulation, we observed larger GCs in mice in which HGAL expression was initiated in GC B cells. All 3 mouse strains developed DLBCL at a frequency of 12% to 30% starting at age 13 months, leading to shorter survival. Immunohistochemical studies showed that all analyzed tumors were of the GC B-cell type. Exon sequencing revealed mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development. •Conditional expression of HGAL in mice leads to lymphoma that resembles human GC B-type DLBCL.•Irrespective of the differential stage at which HGAL is expressed, it leads to a block in B-cell differentiation at the GC reaction. [Display omitted]