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

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. 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. Majority of DLBCL tumors, mainly GC B-cell but also activated types, express HGAL. To investigate the consequences of constitutive expression of HGAL in vivo, we generated mice that conditionally express the human HGAL at different stages of hematopoietic development using three different restricted Cre-mediated approaches to initiate expression of HGAL in hematopoietic stem cells (HSC), pro-B cells or GC B-cells, respectively. Following immune stimulation, we observed larger GCs in mice where HGAL expression was initiated in GC B-cells. All three mouse strains developed DLBCL at a frequency of 12-30% 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 demonstrated mutations reported in human DLBCL. Our data demonstrate that constitutive enforced expression of HGAL leads to DLBCL development.

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