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Graffi murine leukemia virus: molecular cloning and characterization of the myeloid leukemia-inducing agent
1Département des Sciences Biologiques, Université du Québec à Montréal, Canada.
Abstract:
The Graffi murine leukemia virus (MuLV) is a retroviral mixture that induces predominantly myeloid leukemia in several inbred strains of mice. To analyze the viral component responsible for the myeloid leukemogenesis, we cloned several proviruses from a Graffi MuLV-infected cell line. Several infectious molecular clones were obtained that could be classified into two distinct groups of infectious MuLV. Both types of MuLV were nondefective, ecotropic, and NB tropic and induced granulocytic leukemia in BALB/c and NFS mice. Restriction enzyme analysis and molecular hybridization with several MuLV probes on one molecular clone from each group revealed that both groups are closely related to each other but are clearly distinct from all known retroviruses. One component of MuLV, however, induced leukemia with a shorter latency period and harbored a lengthier long terminal repeat. The long terminal repeat of the more leukemogenic component of MuLV had acquired a 60-bp perfect duplication in the U3 region. Analysis of the tumor DNAs with probes for the mouse T-cell receptor and immunoglobulin heavy chain genes revealed frequent rearrangements with one or both probes. This concomitant expression by leukemic cells of markers of different lineages, observed in human leukemias, has been termed "lineage infidelity" and confirms that the latter rearrangements are not restricted to hematopoietic precursors committed to lymphoid differentiation.
Insights
Researchers identified two infectious murine leukemia virus (MuLV) types from Graffi MuLV, both causing myeloid leukemia in mice. A variant with a longer long terminal repeat showed higher leukemogenic potential.
Area of Science:
- Virology
- Oncology
- Molecular Biology
Background:
- Graffi murine leukemia virus (MuLV) is a retroviral mixture known to induce myeloid leukemia in mice.
- Understanding the specific viral components responsible for leukemogenesis is crucial for developing targeted therapies.
Purpose of the Study:
- To isolate and characterize the specific MuLV components responsible for myeloid leukemogenesis.
- To investigate the genetic and molecular features of these MuLV components and their role in leukemia development.
Main Methods:
- Cloning of proviruses from a Graffi MuLV-infected cell line.
- Generation of infectious molecular clones of MuLV.
- Restriction enzyme analysis and molecular hybridization using MuLV probes.
- Analysis of tumor DNA for rearrangements in T-cell receptor and immunoglobulin heavy chain genes.
Main Results:
- Two distinct groups of infectious MuLV were obtained, both capable of inducing granulocytic leukemia.
- These MuLV groups are closely related but distinct from known retroviruses.
- A more leukemogenic MuLV component with a longer long terminal repeat, including a 60-bp duplication in the U3 region, was identified.
- Tumor DNA analysis revealed frequent rearrangements in T-cell receptor and immunoglobulin heavy chain genes, indicating lineage infidelity.
Conclusions:
- The study successfully isolated and characterized infectious MuLV components responsible for myeloid leukemogenesis.
- A specific structural feature in the long terminal repeat (LTR) of MuLV is associated with increased leukemogenic potential.
- The observed lineage infidelity in leukemic cells highlights a conserved mechanism in both murine and human leukemias.