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Characterization of mpl cytoplasmic domain sequences required for myeloproliferative leukemia virus pathogenicity
L Bénit1, G Courtois, M Charon
1INSERM U363, ICGM, Hôpital Cochin, Paris, France.
Abstract:
v-mpl is a truncated form of a receptor-like chain which belongs to the cytokine receptor superfamily. This sequence has been transduced in the myeloproliferative leukemia virus as an env-mpl fusion gene responsible for an acute myeloproliferative disorder in mice. We constructed a series of viral mutants in the mpl sequence. Analysis of their oncogenic potential in vivo indicated that a critical 69-amino-acid-long cytoplasmic domain of v-Mpl is required for myoproliferative leukemia virus pathogenicity. We also developed an in vitro assay and showed that expression of the env-mpl gene confers growth factor independence to murine as well as to human hematopoietic growth factor-dependent cell lines. These findings strongly suggest that v-Mpl delivers a constitutive proliferative signal through a limited region of its cytoplasmic domain.
Insights
The myeloproliferative leukemia virus
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- v-Mpl is a truncated cytokine receptor superfamily member.
- It is transduced by the myeloproliferative leukemia virus (MPLV).
- MPLV causes acute myeloproliferative disorders in mice.
Purpose of the Study:
- To identify the critical domains of v-Mpl responsible for MPLV pathogenicity.
- To investigate the mechanism by which v-Mpl induces cellular proliferation.
Main Methods:
- Construction and analysis of MPLV viral mutants.
- In vivo assessment of oncogenic potential.
- Development of an in vitro cell proliferation assay.
Main Results:
- A specific 69-amino-acid cytoplasmic domain of v-Mpl is essential for MPLV pathogenicity.
- v-Mpl expression confers growth factor independence to hematopoietic cell lines.
- This suggests v-Mpl delivers a constitutive proliferative signal.
Conclusions:
- The critical cytoplasmic domain of v-Mpl is key to MPLV's ability to cause disease.
- v-Mpl signaling drives uncontrolled cell growth in hematopoietic cells.
- Targeting this domain could offer therapeutic strategies for myeloproliferative disorders.