Molecular requirements for rapid plasmacytoma and pre-B lymphoma induction by Abelson murine leukemia virus in myc-transgenic mice.
Mutants and fusion products of the c-abl gene were used to define some of the molecular requirements for rapid plasmacytoma (PC) and pre-B-lymphoma induction in pristane-treated N-myc transgenic BALB/c mice. A-MuLV induced PCs in 21 of 25 mice with a mean post-pristane latency period of 46 +/- 9 days, compared to 134 +/- 25 days in controls exposed to pristane alone. delta XB, a mutant of type IV c-abl with a deletion of the SH3 domain, was equally effective in inducing PCs in 7 of 7 mice with a latency period of 49 +/- 7 days, indicating that gag sequences are not required for rapid PC induction. The delta XB delta Nar mutant that carried a large C-terminal deletion in addition showed only a negligible activity, if any, suggesting that PC acceleration requires the C-terminal domain in the same way as lymphoid transformation and in contrast to fibroblast transformation. BCR-ABL fusion constructs encoding an 185-kDa protein as in acute leukemia, or a 210-kDa protein as in chronic myelocytic leukemia (CML), did not accelerate pristane-induced PC development in the N-myc transgenic mice, in contrast to their known ability to immortalize lymphoid cells in vitro. Only one of 14 non-transgenic littermates developed a pre-B lymphoma after A-MuLV infection, and none of 10 normal littermates infected with delta XB virus developed a construct-carrying tumor. This result suggests that PC acceleration is due to co-operative interaction of the N-myc transgene and activated abl. Infection of N-myc transgenic bone marrow or spleen cells with A-MuLV in vitro led to the outgrowth of pre-B lymphomas after transplantation to pristane-treated BALB/c recipients. The lymphoma-inducing activity of A-MuLV depends on its high titer, since diluted A-MuLV or the lower-titered delta XB induced only PCs under the same conditions. The v-abl, delta XB and BCR-ABL-carrying viruses generated immortalized lymphoblastoid lines in vitro, regardless of the presence of the N-myc transgene, suggesting that lymphoid transformation is a direct function of appropriate abl sequences in contrast to PC acceleration.
Microbiology and Tumorbiology Center (MTC), Karolinska Institute, Stockholm, Sweden.
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H
Sugiyama
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Wang
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P
Jackson
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CL
Sawyers
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G
Klein
D000818:Animals; D001853:Bone Marrow / Q000382:microbiology; D001854:Bone Marrow Cells; D002472:Cell Transformation, Viral / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology; D016313:Genes, abl; D016259:Genes, myc; D009052:Leukemia Virus, Murine / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010954:Plasmacytoma / Q000235:genetics* / Q000382:microbiology*; D011230:Precancerous Conditions / Q000235:genetics* / Q000382:microbiology*; D013154:Spleen / Q000166:cytology / Q000382:microbiology; D013729:Terpenes / Q000494:pharmacology
D013729:Terpenes; C009042:pristane; D016044:Fusion Proteins, bcr-abl