The fetal origin of B-precursor leukemia in the E-mu-ret mouse

Before the clinical onset of B-precursor lymphoblastic leukemia, E-mu-ret mice have an expansion of late pro-B cells (CD45R+CD43(+)CD24(+)BP-1(+)) within the bone marrow. To characterize the early effects of the transgene product on lymphopoiesis, we initially sequenced the Ig heavy chain (IgH) rearrangements within the late pro-B cells in 24-day-old E-mu-ret and transgene negative mice. In both mouse populations, the IgH rearrangements were polyclonal, predominately nonproductive, and exhibited similar V, D, and J gene usage. However, the frequency of N regions, a marker of postnatal lymphopoiesis, was notably different. At the VD junction, N regions were found in 25 of 25 (100. 0%) rearrangements from transgene-negative mice compared with 12 of 36 (33.3%) rearrangements from Emicro-ret mice. At the DJ junction, N regions were found in 21 of 25 (84.0%) rearrangements from transgene negative mice compared with 4 of 36 (11.1%) rearrangements from E-mu-ret mice. Subsequently, we sequenced the clonal IgH rearrangements from 9 leukemias that developed in 10-to 38-week-old mice and found that 7 leukemias had a least 1 rearrangement that lacked N regions at the DJ junction. In addition, V replacement events were observed in the 1 leukemia studied in detail. Terminal deoxynucleotidyl transferase, the enzyme responsible for N region addition, was expressed at markedly lower levels in late pro-B cells from 7- to 10-day-old E-mu-ret mice compared with transgene-negative mice. Examination of fetal lymphopoiesis in E-mu-ret mice identified a relative increase in early (CD45R+CD43(+)CD24(+)BP-1(-)) and late pro-B cells and a decrease in more differentiated CD43(-) B-lineage cells. Fetal early pro-B cells from Emicro-ret mice proliferated threefold to fivefold greater but differentiated to a lesser extent than those from transgene negative mice when cultured in vitro with interleukin-7. These data suggest that the B precursor leukemias in adult E-mu-ret mice arise from the progeny of pro-B cells generated in utero.