B-cell–specific Myd88p.L252P expression drives lymphoproliferation and lymphomagenesis in vivo. (A) B-cell–specific expression of Myd88p.L252P significantly reduces overall survival in vivo. Kaplan-Meier curves illustrate the overall survival of M-Cd19 mice. M-Cd19 mice display a significantly reduced survival compared with the respective controls (log-rank test). (B) Serial MRI scans in 16-, 34-, and 70-week-old M-Cd19 mice revealed the occurrence of splenomegaly in 70-week-old M-Cd19 mice. (C) M-Cd19 mice display splenomegaly at the time of death. Preterminal M-Cd19 and Cd19 mice were sacrificed and spleen weight was recorded. Bars represent the average (n = 3); error bars represent standard deviations. (D) M-Cd19 mice develop lymphoproliferative disease and occasional lymphoma. The top panels show H&E staining of spleens and livers isolated from C57BL/6 and M-Cd19 mice at the time of death. Although the organ architecture appeared normal in C57BL/6 wild-type mice, the architecture of spleens isolated from M-Cd19 mice was largely disrupted by infiltration of small mature lymphocytes (LPD columns) or large blastoid cells (DLBCL columns). The bottom panel shows the partial and complete disruption of the spleen by infiltrates with high proliferative indices. (E) Immunohistochemical characterization of the liver infiltrates of M-Cd19 mice. Areas of infiltrates morphologically resembling DLBCL (marked with solid triangles) showed a homogeneous staining pattern of B220 and Irf4 positivity, whereas they were negative for Bcl6 and Cd138 (bottom panel). Infiltrated areas of small, mature lymphocytes (marked with open triangles) displayed a more heterogeneous staining pattern of positive and negative cells for B220, Irf4, and Cd138, whereas staining was largely negative for Bcl6 (middle panel). (F) The lymphoma cells infiltrating spleens and livers of M-Cd19 mice displayed a largely nuclear localization of p65, indicating NF-κB activation. Black arrows indicate hepatocytes, black arrowheads indicate cytoplasmic p65 staining in splenic lymphocytes in C57BL/6 wild-type mice, and white arrowheads indicate nuclear p65 staining in lymphoma cells in M-Cd19 mice.
