Constitutive Lymphoid Expression of the Nuclear Form of RNase H1 Is Associated with Development of Immature B Cell Lymphomas.

Abstract 1613

Poster Board I-639

Ribonuclease H1, which cleaves the RNA of RNA/DNA hybrids, plays a vital role in the replication of mitochondrial DNA during mouse embryogenesis, but its contributions to later mammalian development and adult biology are not known. In higher eukaryotes two isoforms of RNase H1, a nuclear form and mitochondrial form, are produced from a single transcript. To investigate the effects of constitutive high level RNase H1 expression, we generated transgenic (TG) mice, strain M27F7, with lymphocyte-specific over-expression of nuclear RNase H1. Transcripts in B cells from TG mice were ∼100-fold higher than in wild type B cells. Although there was no obvious phenotype in young mice, some of the older mice, especially females, developed lymphadenopathy, splenomegaly and mediastinal masses and were diagnosed histologically as having lymphoblastic lymphomas. Cell lines established from the tumors were examined by FACS, gene expression profiling and SKY as well as by FISH for Igh and Myc. By FACS criteria, the tumors were B cell lineage and were arrested at the pre-B to immature stage of differentiation. Expression profiles showed the lines to have increased expression of anti-apoptotic genes and genes promoting cell cycle progression. Chromosomal studies revealed no signs of genomic instability or translocations, although there were trisomies of chromosomes 3 and 15. Myc was structurally intact in all lines. These results suggest that RNase H1 plays a previously unappreciated role in early B cell development and that constitutive overexpression contributes to lymphomagenesis.

This work was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute of Allergy and Infectious Diseases.