Importance of receptor usage, Fli1 activation, and mouse strain for the stem cell specificity of 10A1 murine leukemia virus leukemogenicity.
Murine leukemia viruses (MuLV) induce leukemia through a multistage process, a critical step being the activation of oncogenes through provirus integration. Transcription elements within the long terminal repeats (LTR) are prime determinants of cell lineage specificity; however, the influence of other factors, including the Env protein that modulates cell tropism through receptor recognition, has not been rigorously addressed. The ability of 10A1-MuLV to use both PiT1 and PiT2 receptors has been implicated in its induction of blast cell leukemia. Here we show that restricting receptor usage of 10A1-MuLV to PiT2 results in loss of blast cell transformation capacity. However, the pathogenicity was unaltered when the env gene is exchanged with Moloney MuLV, which uses the Cat1 receptor. Significantly, the leukemic blasts express erythroid markers and consistently contain proviral integrations in the Fli1 locus, a target of Friend MuLV (F-MuLV) during erythroleukemia induction. Furthermore, an NB-tropic variant of 10A1 was unable to induce blast cell leukemia in C57BL/6 mice, which are also resistant to F-MuLV transformation. We propose that 10A1- and F-MuLV actually induce identical (erythro)blastic leukemia by a mechanism involving Fli1 activation and cooperation with inherent genetic mutations in susceptible mouse strains. Furthermore, we demonstrate that deletion of the Icsbp tumor suppressor gene in C57BL/6 mice is sufficient to confer susceptibility to 10A1-MuLV leukemia induction but with altered specificity. In summary, we validate the significance of the env gene in leukemia specificity and underline the importance of a complex interplay of cooperating oncogenes and/or tumor suppressors in determining the pathogenicity of MuLV variants.
Rodenburg
Michaela
M
Heinrich-Pette-Institut, Hamburg, Germany.
Fischer
Meike
M
Engelmann
Afra
A
Harbers
Stephanie O
SO
Ziegler
Marion
M
Löhler
Jürgen
J
Stocking
Carol
C
D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000821:virology*; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D007942:Leukemia, Experimental / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D012192:Retroviridae Infections / Q000473:pathology / Q000821:virology; D013045:Species Specificity; D014412:Tumor Virus Infections / Q000473:pathology / Q000821:virology
C497426:Fli1 protein, mouse; D015686:Gene Products, env; D051789:Proto-Oncogene Protein c-fli-1; D011991:Receptors, Virus