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

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.

Download Full-text

Distinct chromosomal abnormalities in murine leukemia virus-induced T- and B-cell lymphomas

International Journal of Cancer ◽

10.1002/ijc.2910430626 ◽

1989 ◽

Vol 43 (6) ◽

pp. 1112-1119 ◽

Cited By ~ 5

Author(s):

W. L. E. Vasmel ◽

E. A. Matthews ◽

C. P. M. Gillis ◽

J. Nieland ◽

E. A. Borst ◽

...

Keyword(s):

B Cell ◽

Murine Leukemia Virus ◽

Chromosomal Abnormalities ◽

Leukemia Virus ◽

B Cell Lymphomas ◽

Murine Leukemia

Download Full-text

Identification of a common viral integration region in Cas-Br-E murine leukemia virus-induced non-T-, non-B-cell lymphomas.

Journal of Virology ◽

10.1128/jvi.65.1.7-15.1991 ◽

1991 ◽

Vol 65 (1) ◽

pp. 7-15 ◽

Cited By ~ 29

Author(s):

D Bergeron ◽

L Poliquin ◽

C A Kozak ◽

E Rassart

Keyword(s):

B Cell ◽

Murine Leukemia Virus ◽

Leukemia Virus ◽

Viral Integration ◽

B Cell Lymphomas ◽

Integration Region ◽

Murine Leukemia

Download Full-text

The Icsbp locus is a common proviral insertion site in mature B-cell lymphomas/plasmacytomas induced by exogenous murine leukemia virus

Virology ◽

10.1016/j.virol.2006.05.006 ◽

2006 ◽

Vol 352 (2) ◽

pp. 306-318 ◽

Cited By ~ 3

Author(s):

Shi Liang Ma ◽

Annette Balle Sørensen ◽

Sandra Kunder ◽

Karina Dalsgaard Sørensen ◽

Leticia Quintanilla-Martinez ◽

...

Keyword(s):

B Cell ◽

Murine Leukemia Virus ◽

Leukemia Virus ◽

Insertion Site ◽

B Cell Lymphomas ◽

Murine Leukemia

Download Full-text

Murine Leukemia Virus Proviral Insertions between the N-ras and unr Genes in B-Cell Lymphoma DNA Affect the Expression of N-ras Only

Journal of Virology ◽

10.1128/jvi.75.23.11907-11912.2001 ◽

2001 ◽

Vol 75 (23) ◽

pp. 11907-11912 ◽

Cited By ~ 13

Author(s):

Javier Martı́n-Hernández ◽

Annette Balle Sørensen ◽

Finn Skou Pedersen

Keyword(s):

B Cell ◽

Murine Leukemia Virus ◽

Leukemia Virus ◽

Latency Period ◽

Pcr Amplification ◽

B Cell Lymphoma ◽

Northern Blotting ◽

B Cell Lymphomas ◽

Exon 1 ◽

Murine Leukemia

ABSTRACT Akv1-99, a variant of Akv murine leukemia virus, induces B-cell lymphomas with nearly 100% incidence and a mean latency period of 12 months after injection into newborn NMRI mice. PCR amplification and sequence analyses of DNA flanking integrated proviruses revealed proviral insertion into the N-ras/unr (upstream of N-ras) locus in 2 out of 13 B-cell lymphomas, both of which appeared clonal by Southern blotting analysis. These two tumors showed increased expression levels of N-ras by Northern blotting, as did a third tumor shown by reverse transcriptase PCR to have a nonclonal provirus integration located in the same area. However, no significant changes in expression were observed when using a specific probe for the unr gene. All proviruses were integrated in the same transcriptional orientation as unr and N-ras genes. By promoter insertion, the two Akv1-99 proviruses integrated between exon −1 and exon 1 of N-rasgave rise to two different spliced products, whereas the provirus integrated into unr used only an exon skipping pattern. The absence of mutations of the N-ras codons 12, 13, 18, and 61 suggests that activation of the proto-oncogene is exclusively due to overexpression by retroviral promoter insertion, and furthermore, Northern blot analyses indicate that the expression of unris unaffected by N-ras overexpression even in the case where the unr gene itself is the target of proviral insertion. Thus, altogether our findings indicate that overexpression of N-ras plays a role in development of murine leukemia virus-induced B-cell lymphomas, leaving the expression of the tightly linked unr gene unaltered.

Download Full-text

Tumorigenic Potential of a Recombinant Retrovirus Containing Sequences from Moloney Murine Leukemia Virus and Feline Leukemia Virus

Journal of Virology ◽

10.1128/jvi.72.2.1078-1084.1998 ◽

1998 ◽

Vol 72 (2) ◽

pp. 1078-1084 ◽

Cited By ~ 14

Author(s):

C. R. Starkey ◽

P. A. Lobelle-Rich ◽

S. Granger ◽

B. K. Brightman ◽

H. Fan ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Murine Leukemia Virus ◽

Cell Lymphoma ◽

Leukemia Virus ◽

T Cell Lymphoma ◽

Domestic Cat ◽

Moloney Murine Leukemia Virus ◽

B Cell Lymphomas ◽

Murine Leukemia

ABSTRACT A recombinant retrovirus, termed MoFe2-MuLV, was constructed in which the U3 region of T-lymphomagenic Moloney murine leukemia virus (Mo-MuLV) was replaced by that of FeLV-945, a provirus of unique long terminal repeat (LTR) structure identified only in non-T-cell, non-B-cell lymphomas of the domestic cat. The LTR of FeLV-945 is unusual in that it contains only a single copy of the transcriptional enhancer followed 25 bp downstream by a 21-bp sequence in triplicate in tandem. Infectivity of MoFe2-MuLV was demonstrated in vitro in SC-1 cells and in vivo in neonatal NIH-Swiss mice. Tumors occurred in MoFe2-MuLV-infected animals following a latency period of 4 to 10 months (average, 6 months). The results of Southern blot analysis of the T-cell receptor beta locus demonstrated that all tumors were lymphomas of T-cell origin. MoFe2-MuLV LTRs were amplified by PCR from tumor DNA and were characterized by nucleotide sequence analysis. LTRs from the tumors that occurred with relatively shorter latency predominantly retained the original MoFe2-MuLV sequence intact and unaltered. Tumors that occurred with relatively longer latency contained LTRs that also retained the 21-bp sequence triplication characteristic of the original virus but had acquired various duplications of enhancer sequences. The repeated identification of enhancer duplications in late-appearing tumors suggests that the duplication affords a selective advantage, although apparently not in the efficient induction of T-cell lymphoma. Proto-oncogenes known to be targets of insertional mutagenesis in the majority of Mo-MuLV-induced tumors or in feline non-T-cell, non-B-cell lymphomas were shown not to be rearranged in any tumor examined. Mink cell focus-inducing (MCF) proviral DNA was readily detectable in some, but not all, tumors. The presence or absence of MCF did not correlate with the kinetics of tumor induction. These studies indicate that the single-enhancer, triplication-containing FeLV LTR, typical of non-T-cell, non-B-cell lymphomas in cats, is competent in the induction of T-cell lymphoma in mice. The findings suggest that the mechanism of MoFe2-MuLV-mediated lymphomagenesis may differ from that of Mo-MuLV-mediated disease, considering the possible involvement of novel oncogenes and the variable presence of MCF recombinants.

Download Full-text