A MODEL FOR SPONTANEOUS B-LINEAGE LYMPHOMAS IN IGH-MU-HOX11 TRANSGENIC MICE

HOX11, a divergent homeodomain-containing transcription factor, was is olated from the breakpoint of the nonrandom t(10;14)(q24;q11) chromoso me translocation found in human T cell acute lymphoblastic leukemias. The translocation places the HOX11 coding sequence under the transcrip tional control of TCR alpha/delta regulatory elements, resulting in ec topic expression of a normal HOX11 protein in thymocytes. To investiga te the oncogenic potential of HOX11, we targeted its expression in lym phocytes of transgenic mice by placing the human cellular DNA under th e transcriptional control of Ig heavy chain or LCK regulatory sequence s. Only IgH(mu)-HOX11 mice expressing low levels of HOX11 were viable. During their second year of life, all HOX11 transgenic mice became te rminally ill with more than 75% developing large cell lymphomas in the spleen, which frequently disseminated to thymus, lymph nodes, and oth er nonhematopoietic tissues. Lymphoma cells were predominantly clonal IgM(+)IgD(+) mature B cells, Repopulation of severe combined immunodef icient mice with cells from hyperplastic spleens indicated that the HO X11 tumor phenotype was transplantable. Before tumor development, expr ession of the transgene did not result in perturbations in lymphopoies is; hoc-ever, lymphoid hyperplasia involving the splenic marginal zone s,vas present in 20% of spleens. Our studies pro,ide direct evidence t hat expression of HOX11 in lymphocytes leads to malignant transformati on. These mice are a useful model system to study mechanisms involved in transformation from B-lineage hyperplasia to malignant lymphoma and for testing novel approaches to therapy. They represent a novel anima l model for non-Hodgkin's lymphoma of peripheral mature B cell origin.