In vitro transformation of murine pro-B and pre-B cells by v-mpl, a truncated form of a cytokine receptor.
v-mpl is a constitutively activated, truncated form of a cytokine receptor that has been transduced in a murine retrovirus, the myeloproliferative leukemia virus (MPLV). Expression of this oncogene results in the factor-independent proliferation of myeloid, erythroid, megakaryocytic, and mast precursor cells, which retain the ability to differentiate. However, no lymphoid disease was ever reported. To determine whether MPLV could infect and transform very early B cells and their precursors (BCPs), lymphoid long-term bone marrow cultures were infected with a helper-free MPLV. Within 3 wk after infection, highly proliferating BCPs could be isolated. These cells were able to clone spontaneously in semi-solid cultures, grown in the absence of feeder cell layer or exogenous growth factor and rapidly produced tumors after s.c. injection into synegic irradiated mice. In addition, MPLV transformation of pre-B cells led to the induction of an autocrine activity. Immunophenotypic and molecular analysis indicated that MPLV transformed early pro-B, pro-B, and pre-B cells, according to the expression of HSA, CD43, B220, Thy1, s-IgM and BP1 Ags, and to the rearrangements of Ig genes. Interestingly, MPLV-transformed BCPs expressed Mac1 Ag without acquiring further characteristics of macrophagic differentiation. Although the v-mpl cytoplasmic domain is devoid of tyrosine kinase consensus sequence, MPLV-transformed pre-B cells contained a major approximately 105-kDa tyrosine-phosphorylated protein that was not detected in uninfected cells or in cells transformed by the Abelson viral oncogene (v-abl). These results demonstrate that, like v-abl, the truncated cytokine receptor v-mpl is able to transform BCPs in vitro and suggest that the oncogenic transformation of BCPs by either v-mpl or v-abl use different pathways.
INSERM U363, ICGM, René Descartes University, Paris, France.
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S
Fichelson
I
I
Vigon
I
I
Dusanter
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M
Charon
T
T
Velu
C
C
Baillou
S
S
Gisselbrecht
F M
FM
Lemoine
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000821:virology*; D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division; D002461:Cell Line, Transformed / Q000637:transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D006412:Hematopoietic Stem Cells / Q000821:virology*; D009052:Leukemia Virus, Murine / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D016374:Oncogene Proteins v-abl / Q000502:physiology; D009857:Oncogenes; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000502:physiology*
D000943:Antigens, Differentiation; D017077:Culture Media, Conditioned; D016374:Oncogene Proteins v-abl; D010750:Phosphoproteins; D018121:Receptors, Cytokine; D011505:Protein-Tyrosine Kinases