scholarly journals 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

2004 ◽  
Vol 78 (23) ◽  
pp. 13216-13231 ◽  
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.

scholarly journals Novel Insights into the Pathogenesis of the Graffi Murine Leukemia Retrovirus

2006 ◽  
Vol 80 (8) ◽  
pp. 4026-4037 ◽  
Author(s):  
Véronique Voisin ◽  
Corinne Barat ◽  
Trang Hoang ◽  
Eric Rassart
Keyword(s):  
B Cell ◽  
Murine Leukemia Virus ◽  
Myeloid Leukemia ◽  
Morphological Analysis ◽  
Leukemia Virus ◽  
Blood Smears ◽  
Myeloid Leukemias ◽  
Disease Specificity ◽  
Different Strains ◽  
Murine Leukemia

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.

scholarly journals Moloney Murine Leukemia Virus-Induced Tumors Show Altered Levels of Proapoptotic and Antiapoptotic Proteins

2000 ◽  
Vol 74 (17) ◽  
pp. 8151-8158 ◽  
Author(s):  
Christine Bonzon ◽  
Hung Fan
Keyword(s):  
Tumor Cells ◽  
Murine Leukemia Virus ◽  
Fas Ligand ◽  
Leukemia Virus ◽  
Moloney Murine Leukemia Virus ◽  
Cell Surface Expression ◽  
Color Flow ◽  
Induced Tumors ◽  
Ligand Expression ◽  
Murine Leukemia

ABSTRACT Moloney murine leukemia virus (M-MuLV) is a replication-competent, simple retrovirus that induces T-cell lymphomas when inoculated into neonatal mice. The tumor cells are typically derived from immature T cells. During preleukemic times, a marked decrease in thymic size is apparent in M-MuLV-inoculated mice. We previously demonstrated that this thymic regression is correlated with enhanced levels of thymocyte apoptosis (C. Bonzon and H. Fan, J. Virol. 73:2434-2441, 1999). In this study, we investigated the apoptotic state of M-MuLV-induced tumors. M-MuLV-induced tumors were screened for expression of the apoptotic proteins Fas and Bcl-2 by three-color flow cytometric analysis. Single-positive (SP; CD4+ CD8− and CD4−CD8+) tumor cells generally displayed lower cell surface expression of Fas than SP thymocytes from uninoculated control mice. Double-positive (DP; CD4+ CD8+) M-MuLV-induced tumor cells fell into two categories: those with normal high levels of Fas and those with low levels of Fas. Additionally, the vast majority of DP tumors showed elevated Bcl-2 levels. The DP tumor cells retaining normal/high Fas expression were capable of transducing an apoptotic signal upon anti-Fas engagement. In addition, DP and CD4+SP tumor populations displayed higher levels of Fas ligand than normal thymocytes with the same phenotypes. In contrast, CD8+ SP and CD4− CD8− tumors did not show elevated Fas ligand expression. There was no significant correlation between Fas and Fas ligand expression in the DP tumors, suggesting that Fas Ligand expression was not the driving force behind Fas down-regulation. These results suggest that both the Fas death receptor and mitochondrial pathways of apoptotic death are active in M-MuLV-induced tumors and that they must be modulated to permit cell survival and tumor outgrowth.

Tumor progression in murine leukemia virus-induced T-cell lymphomas: monitoring clonal selections with viral and cellular probes.

1986 ◽  
Vol 60 (1) ◽  
pp. 230-241 ◽  
Author(s):  
H T Cuypers ◽  
G C Selten ◽  
M Zijlstra ◽  
R E de Goede ◽  
C J Melief ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Progression ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
T Cell Lymphomas ◽  
Cellular Probes ◽  
Murine Leukemia

Stability of AML1 (core) site enhancer mutations in T lymphomas induced by attenuated SL3-3 murine leukemia virus mutants.

1997 ◽  
Vol 71 (7) ◽  
pp. 5080-5087 ◽  
Author(s):  
H W Amtoft ◽  
A B Sørensen ◽  
C Bareil ◽  
J Schmidt ◽  
A Luz ◽  
...  
Keyword(s):  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Core Site ◽  
T Lymphomas ◽  
Murine Leukemia

scholarly journals Specificity studies on cytolytic T lymphocytes directed against murine leukemia virus-induced tumors. Analysis of monoclonal cytolytic T lymphocytes.

1982 ◽  
Vol 155 (4) ◽  
pp. 1050-1062 ◽  
Author(s):  
F Plata
Keyword(s):  
T Lymphocytes ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Target Cells ◽  
Cytolytic T Lymphocytes ◽  
Tumor Target ◽  
Induced Tumors ◽  
Definition Of ◽  
Leukemia Viruses ◽  
Murine Leukemia

The specificities of cloned cytolytic T lymphocytes (CTL) were studied for the analysis of CTL populations generated against murine leukemia viruses (MuLV) in H-2 congenic BALB/c (H-2d) and BALB.B (H-2b) mice. In particular, CTL generated in response to tumors induced by Gross MuLV and Friend MuLV were studied; these tumors expressed virus-induced antigens that do not cross-react and that can be distinguished from each other. The systematic study of 92 CTL clones clearly indicated that MuLV-immune CTL were highly heterogeneous with respect to both the intensities of target cell lysis that they mediated and to their specificity of recognition of MuLV-induced tumor target cells. Various categories of CTL clones were identified, ranging from CTL clones tht were tightly H-2 restricted and specific for the immunizing tumor to CTL clones that displayed no discernible patterns of specificity and that attacked a large number of different target cells. In addition, the surface markers of these cloned CTL were defined, and the best conditions for their prolonged maintenance in culture were determined. The present data indicate that future efforts in the definition of target antigens recognized by tumor-specific CTL should be performed with monoclonal lymphocytes.

scholarly journals Differential disease restriction of Moloney and Friend murine leukemia viruses by the mouse Rmcf gene is governed by the viral long terminal repeat.

1991 ◽  
Vol 174 (2) ◽  
pp. 389-396 ◽  
Author(s):  
B K Brightman ◽  
Q X Li ◽  
D J Trepp ◽  
H Fan
Keyword(s):  
Long Terminal Repeat ◽  
Murine Leukemia Virus ◽  
Time Course ◽  
Leukemia Virus ◽  
Terminal Repeat ◽  
Moloney Murine Leukemia Virus ◽  
Erythroid Progenitors ◽  
Equivalent Time ◽  
Induced Tumors ◽  
Murine Leukemia

Neonatal CxD2 (Rmcfr) and Balb/c (Rmcfs) mice inoculated with Moloney murine leukemia virus (M-MuLV) exhibited approximately equivalent time course and pathology for disease. CxD2 mice showed only slightly reduced presence of Moloney mink cell focus-forming virus (M-MCF) provirus as seen by Southern blot analysis compared to Balb/c mice. This lack of restriction for disease and spread of MCF was in sharp contrast to that seen for CxD2 mice inoculated with Friend murine leukemia virus (F-MuLV), where incidence of disease and propagation of MCFs were severely restricted, as previously reported. Inoculation of CxD2 mice with FM-MuLV, a recombinant F-MuLV virus containing M-MuLV LTR sequences (U3 and R), resulted in T cell disease of time course equal to that seen in Balb/c mice; there also was little restriction for propagation of MCFs. This indicated that presence of the M-MuLV long terminal repeat (LTR) was sufficient for propagation of MCFs in CxD2 mice. Differing restriction for F-MuLV vs. M-MuLV in CxD2 mice was explained on the basis of different "MCF propagator cells" for the two viruses. It was suggested that cells propagating F-MCF (e.g., erythroid progenitors) are blocked by endogenous MCF-like gp70env protein, whereas cells propagating M-MCF (e.g., lymphoid) do not express this protein on their surface. F-MuLV disease in CxD2 mice was greatly accelerated when neonates were inoculated with a F-MuLV/F-MCF pseudotypic mixture. However, F-MCF provirus was not detectable or only barely detectable in F-MuLV/F-MCF-induced tumors, suggesting that F-MCF acted indirectly in induction of these tumors.

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