Mutation of all Runx (AML1/core) sites in the enhancer of T-lymphomagenic SL3-3 murine leukemia virus unmasks a significant potential for myeloid leukemia induction and favors enhancer evolution toward induction of other disease patterns.
SL3-3 murine leukemia virus is a potent inducer of T-lymphomas in mice. Using inbred NMRI mice, it was previously reported that a mutant of SL3-3 with all enhancer Runx (AML1/core) sites disrupted by 3-bp mutations (SL3-3dm) induces predominantly non-T-cell tumors with severely extended latency (S. Ethelberg, J. Lovmand, J. Schmidt, A. Luz, and F. S. Pedersen, J. Virol. 71:7273-7280, 1997). By use of three-color flow cytometry and molecular and histopathological analyses, we have now performed a detailed phenotypic characterization of SL3-3- and SL3-3dm-induced tumors in this mouse strain. All wild-type induced tumors had clonal T-cell receptor beta rearrangements, and the vast majority were CD3(+) CD4(+) CD8(-) T-lymphomas. Such a consistent phenotypic pattern is unusual for murine leukemia virus-induced T-lymphomas. The mutant virus induced malignancies of four distinct hematopoietic lineages: myeloid, T lymphoid, B lymphoid, and erythroid. The most common disease was myeloid leukemia with maturation. Thus, mutation of all Runx motifs in the enhancer of SL3-3 severely impedes viral T-lymphomagenicity and thereby discloses a considerable and formerly unappreciated potential of this virus for myeloid leukemia induction. Proviral enhancers with complex structural alterations (deletions, insertions, and/or duplications) were found in most SL3-3dm-induced T-lymphoid tumors and immature myeloid leukemias but not in any cases of myeloid leukemia with maturation, mature B-lymphoma, or erythroleukemia. Altogether, our results indicate that the SL3-3dm enhancer in itself promotes induction of myeloid leukemia with maturation but that structural changes may arise in vivo and redirect viral disease specificity to induction of T-lymphoid or immature myeloid leukemias, which typically develop with moderately shorter latencies.
Sørensen
Karina Dalsgaard
KD
Department of Molecular Biology, University of Aarhus, C. F. Møllers Allé, Bldg. 130, DK-8000 Aarhus C, Denmark.
Quintanilla-Martinez
Leticia
L
Kunder
Sandra
S
Schmidt
Jörg
J
Pedersen
Finn Skou
FS
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001483:Base Sequence; D039481:CD11b Antigen / Q000032:analysis; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000502:physiology*; D004198:Disease Susceptibility; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D009052:Leukemia Virus, Murine / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000209:etiology*; D051917:Leukosialin; D016399:Lymphoma, T-Cell / Q000209:etiology; D051379:Mice; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012795:Sialoglycoproteins / Q000032:analysis; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014157:Transcription Factors / Q000502:physiology*
D015703:Antigens, CD; D039481:CD11b Antigen; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D051917:Leukosialin; D011518:Proto-Oncogene Proteins; C493726:Runx1 protein, mouse; D012795:Sialoglycoproteins; C497863:Spn protein, mouse; D014157:Transcription Factors