The evolution of B precursor leukemia in the Emu-ret mouse

Emu-ret mice carrying an RFP/RET fusion gene under the transcriptional control of the immunoglobulin heavy chain enhancer develop B lineage leukemias/lymphomas. We have characterized B-cell development in these mice before the onset of clinical disease to determine the steps involved in leukemogenesis. Flow cytometry reveals that the CD45R+CD43(+)CD24(+)BP-1(+) late pro-B-cell population is markedly expanded in the bone marrow of 3- to 5-week-old Emu-ret mice. Compared with late pro-B cells from transgene-negative mice, Emu-ret late pro-B cells have a limited capacity to differentiate in interleukin (IL)-7 and a higher incidence of VDJ rearrangements, but a similar cell cycle profile. In contrast, CD45R+CD43(+)CD24(+)BP-1(-) early pro-B cells from 3- to 5-week-old Emu-ret mice, which also express the RFP/RET transgene, differentiate in IL-7 similarly to their normal counterparts. Furthermore, early pro-B cells from Emu-ret and transgene-negative mice have an identical pattern of growth inhibition when exposed to interferons (IFNs)-alpha/beta and -gamma, whereas, pro-B-cell leukemia lines derived from Emu-ret mice are markedly less sensitive to growth inhibition by these IFNs. In 13-week-old well-appearing Emu-ret mice, late pro-B cells upregulate CYCLIN D1 expression and downregulate CASPASE-1 expression in a pattern that correlates with the emergence of B precursor cells in the peripheral blood and the loss of other B lineage subsets in the bone marrow. Taken together, these results suggest that the expression of the RFP/RET transgene initially prevents the normal elimination of late pro-B cells with nonproductive rearrangements. Secondary events that simultaneously disturb the normal transcriptional regulation of genes involved in the control of the cell cycle and apoptosis may allow for subsequent malignant transformation within the expanded late pro-B-cell population.