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.
Zeng
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Division of Oncology, The Children's Hospital of Philadelphia, and Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Zhang
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Hardy
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RR
Wasserman
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R
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000196:embryology / Q000473:pathology; D002454:Cell Differentiation; D004253:DNA Nucleotidylexotransferase / Q000096:biosynthesis / Q000235:genetics; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015973:Gene Expression Regulation, Leukemic; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000196:embryology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000166:cytology; D016133:Polymerase Chain Reaction; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000196:embryology* / Q000235:genetics; D011519:Proto-Oncogenes; D045567:VDJ Recombinases
D007148:Immunoglobulin mu-Chains; D009363:Neoplasm Proteins; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases; D004253:DNA Nucleotidylexotransferase