Novel Insights into the Pathogenesis of the Graffi Murine Leukemia Retrovirus

ABSTRACT The Graffi murine leukemia virus (MuLV) was isolated in 1954 by Arnold Graffi, who characterized it as a myeloid leukemia-inducing retrovirus. He and his team, however, soon observed the intriguing phenomenon of hematological diversification, which corresponded to a decrease of myeloid leukemias and an increase of other types of leukemias. Recently, we derived two different molecular clones corresponding to ecotropic nondefective genomes that were named GV-1.2 and GV-1.4. The induced leukemias were classified as myeloid based on morphological analysis of blood smears. In this study, we further characterized the two variants of the Graffi murine retrovirus, GV-1.2 and GV-1.4, in three different strains of mice. We show that the Graffi MuLV is a multipotent retrovirus capable of inducing both lymphoid (T- and B-cell) and nonlymphoid (myeloid, erythroid, megakaryocytic) leukemia. Many of these are very complex with concomitant expression of different hematopoietic lineages. Interestingly, a high percentage of megakaryocytic leukemias, a type of leukemia rarely observed with MuLVs, arise in the FVB/n strain of mice. The genetic backgrounds of the different strains of mice influence greatly the results. Furthermore, the enhancer region, different for GV-1.2 and GV-1.4, plays a pivotal role in the disease specificity: GV-1.2 induces more lymphoid leukemias, and GV-1.4 induces more nonlymphoid ones.

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Enhancer mutations of Akv murine leukemia virus inhibit the induction of mature B-cell lymphomas and shift disease specificity towards the more differentiated plasma cell stage

Virology ◽

10.1016/j.virol.2006.12.016 ◽

2007 ◽

Vol 362 (1) ◽

pp. 179-191 ◽

Cited By ~ 8

Author(s):

Karina Dalsgaard Sørensen ◽

Sandra Kunder ◽

Leticia Quintanilla-Martinez ◽

Jonna Sørensen ◽

Jörg Schmidt ◽

...

Keyword(s):

B Cell ◽

Plasma Cell ◽

Murine Leukemia Virus ◽

Leukemia Virus ◽

B Cell Lymphomas ◽

Cell Stage ◽

Disease Specificity ◽

Murine Leukemia

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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

Journal of Virology ◽

10.1128/jvi.78.23.13216-13231.2004 ◽

2004 ◽

Vol 78 (23) ◽

pp. 13216-13231 ◽

Cited By ~ 14

Author(s):

Karina Dalsgaard Sørensen ◽

Leticia Quintanilla-Martinez ◽

Sandra Kunder ◽

Jörg Schmidt ◽

Finn Skou Pedersen

Keyword(s):

T Cell ◽

Murine Leukemia Virus ◽

Myeloid Leukemia ◽

Leukemia Virus ◽

Color Flow ◽

Potent Inducer ◽

Induced Tumors ◽

Myeloid Leukemias ◽

T Lymphomas ◽

Murine Leukemia

ABSTRACT 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 β 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.

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