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Introduction of a cis-acting mutation in the capsid-coding gene of moloney murine leukemia virus extends its
1Institut de Génétique Moléculaire de Montpellier (IGMM), IFR24, CNRS-UMR5535, and Université Montpellier II, F-34293 Montpellier Cedex 5, France.
Abstract:
Inoculation of newborn mice with the retrovirus Moloney murine leukemia virus (MuLV) results in the exclusive development of T lymphomas with gross thymic enlargement. The T-cell leukemogenic property of Moloney MuLV has been mapped to the U3 enhancer region of the viral promoter. However, we now describe a mutant Moloney MuLV which can induce the rapid development of a uniquely broad panel of leukemic cell types. This mutant Moloney MuLV with synonymous differences (MSD1) was obtained by introduction of nucleotide substitutions at positions 1598, 1599, and 1601 in the capsid gene which maintained the wild-type (WT) coding potential. Leukemias were observed in all MSD1-inoculated animals after a latency period that was shorter than or similar to that of WT Moloney MuLV. Importantly, though, only 56% of MSD1-induced leukemias demonstrated the characteristic thymoma phenotype observed in all WT Moloney MuLV leukemias. The remainder of MSD1-inoculated animals presented either with bona fide clonal erythroid or myelomonocytic leukemias or, alternatively, with other severe erythroid and unidentified disorders. Amplification and sequencing of U3 and capsid-coding regions showed that the inoculated parental MSD1 sequences were conserved in the leukemic spleens. This is the first report of a replication-competent MuLV lacking oncogenes which can rapidly lead to the development of such a broad range of leukemic cell types. Moreover, the ability of MSD1 to transform erythroid and myelomonocytic lineages is not due to changes in the U3 viral enhancer region but rather is the result of a cis-acting effect of the capsid-coding gag sequence.
Insights
A new Moloney murine leukemia virus (MuLV) mutant, MSD1, rapidly induces diverse leukemias in mice, including T-cell lymphomas, erythroid, and myelomonocytic types. This broad oncogenic potential stems from its capsid gene, not the viral enhancer region.
Area of Science:
- * Retroviral oncogenesis
- * Murine leukemia virus (MuLV) research
- * Cancer stem cell biology
Background:
- * Wild-type Moloney murine leukemia virus (MuLV) exclusively causes T-cell lymphomas.
- * The T-cell leukemogenic property is linked to the U3 enhancer region of the viral promoter.
- * A need exists to understand viral mechanisms driving diverse leukemic cell types.
Purpose of the Study:
- * To investigate a novel Moloney MuLV mutant (MSD1) capable of inducing a broader spectrum of leukemias.
- * To identify the genetic basis for MSD1's altered leukemogenic potential.
- * To determine if MSD1's oncogenic activity is linked to the U3 enhancer or capsid gene.
Main Methods:
- * Inoculation of newborn mice with wild-type (WT) Moloney MuLV and the MSD1 mutant.
- * Monitoring of leukemic development, latency periods, and phenotypic presentation.
- * Amplification and sequencing of viral U3 and capsid-coding regions from leukemic spleens.
Main Results:
- * MSD1 induced leukemias in all inoculated animals with shorter or similar latency compared to WT MuLV.
- * Only 56% of MSD1-induced leukemias showed the characteristic thymoma phenotype; others were erythroid or myelomonocytic.
- * The MSD1 mutations in the capsid gene were conserved in leukemic cells, and U3 region changes were not observed.
Conclusions:
- * MSD1 is the first replication-competent MuLV lacking oncogenes to rapidly cause diverse leukemias.
- * MSD1's ability to transform erythroid and myelomonocytic lineages is due to a cis-acting effect of the capsid-coding gag sequence.
- * This finding expands the understanding of retroviral oncogenesis beyond enhancer-driven T-cell transformation.