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. 1982 Aug 1;156(2):398–414. doi: 10.1084/jem.156.2.398

Erythroleukemia induction by Friend leukemia virus. A host gene locus controlling early anemia or polycythemia and the rate of proliferation of late erythroid cells

PMCID: PMC2186760  PMID: 7097158

Abstract

This report confirms that the Fv-5 locus controls the types of erythropoiesis induced by Friend erythroleukemia virus (FLV) (21) and extends the study to investigate the mode of action of this locus. With the use of FLV obtained by a variety of procedures, we showed that the polycythemia spleen focus-forming component (SFFVp) was responsible for the contrasting changes of hematocrits observed in FV-Pp (polycythemia strain)-infected DBA/2 (Fv-5pp) or CBA (Fv-5aa) mice. These changes in hematocrits were found to be a direct result of the rise in circulating reticulocytes and erythrocytes in DBA/2 mice and a corresponding drop of these erythroid cells in CBA mice 2 wk after infection. Examination of the FV-P-induced cellular changes indicated that dramatic increase in erythropoietin (epo)-independent erythroid precursor (CFU-E*) cells was detected in the spleens and marrow of both strains of mice. The epo responsiveness of the CFU-E in the uninfected and FV-P-infected CBA and DBA/2 mice was also very similar. Similar to FLV-infected DBA/2 mice, the FV-P-infected CBA mice also developed tumorogenic cells (CFU-FV) relatively early after infection (4-6 wk). Study of the physiological and pathological changes in the marrows and spleens of these infected mice indicated that significant differences were found in the spleens of the two strains of mice. The percent of reticulocytes in the spleen cells of CBA mice remained between 10 and 20%, and level of the DBA/2 mice increased to approximately 50%. This higher rate of erythropoiesis was also reflected in the significantly higher rate of uptake of 59Fe in the spleens of the DBA/2 mice. These results suggest that the Fv-5 locus might control the hematocrit levels of these mice by regulating the rates of erythropoiesis in the spleen levels of these mice, probably by affecting the rate of proliferation of an erythroid cell or cells. The erythroid cell(s) affected is likely to be more mature than the erythroid progenitor, CFU-E, as the levels of CFU-E in these two strains of mice were similar. The hypothesis that Fv-5 may control the rates of proliferation of a late erythroid (cell(s) is also supported by the significantly higher spleen weights found in the infected DBA/2 (approximately 2.5 g/spleen) mice than in the CBA (approximately 1 g/spleen) strain.

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Selected References

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  1. AXELRAD A. A., STEEVES R. A. ASSAY FOR FRIEND LEUKEMIA VIRUS: RAPID QUANTITATIVE METHOD BASED ON ENUMERATION OF MACROSCOPIC SPLEEN FOCI IN MICE. Virology. 1964 Nov;24:513–518. doi: 10.1016/0042-6822(64)90199-0. [DOI] [PubMed] [Google Scholar]
  2. Bennett M., Steeves R. A., Cudkowicz G., Mirand E. A., Russell L. B. Mutant Sl alleles of mice affect susceptibility to Friend spleen focus-forming virus. Science. 1968 Nov 1;162(3853):564–565. doi: 10.1126/science.162.3853.564. [DOI] [PubMed] [Google Scholar]
  3. FRIEND C. Cell-free transmission in adult Swiss mice of a disease having the character of a leukemia. J Exp Med. 1957 Apr 1;105(4):307–318. doi: 10.1084/jem.105.4.307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. FRIEND C., HADDAD J. R. Tumor formation with transplants of spleen or liver from mice with virus-induced leukemia. J Natl Cancer Inst. 1960 Dec;25:1279–1285. [PubMed] [Google Scholar]
  5. Horoszewicz J. S., Leong S. S., Carter W. A. Friend leukemia: rapid development of erythropoietin-independent hematopoietic precursors. J Natl Cancer Inst. 1975 Jan;54(1):265–267. doi: 10.1093/jnci/54.1.265. [DOI] [PubMed] [Google Scholar]
  6. Jolicoeur P., Baltimore D. Effect of Fv-1 gene product on proviral DNA formation and integration in cells infected with murine leukemia viruses. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2236–2240. doi: 10.1073/pnas.73.7.2236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. LILLY F., BOYSE E. A., OLD L. J. GENETIC BASIS OF SUSCEPTIBILITY TO VIRAL LEUKAEMOGENESIS. Lancet. 1964 Dec 5;2(7371):1207–1209. doi: 10.1016/s0140-6736(64)91043-8. [DOI] [PubMed] [Google Scholar]
  8. Liao S. K., Axelrad A. A. Erythropoietin-independent erythroid colony formation in vitro by hemopoietic cells of mice infected with friend virus. Int J Cancer. 1975 Mar 15;15(3):467–482. doi: 10.1002/ijc.2910150313. [DOI] [PubMed] [Google Scholar]
  9. Lilly F. The effect of histocompatibility-2 type on response to friend leukemia virus in mice. J Exp Med. 1968 Mar 1;127(3):465–473. doi: 10.1084/jem.127.3.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Linemeyer D. L., Ruscetti S. K., Menke J. G., Scolnick E. M. Recovery of biologically active spleen focus-forming virus from molecularly cloned spleen focus-forming virus-pBR322 circular DNA by cotransfection with infectious type C retroviral DNA. J Virol. 1980 Sep;35(3):710–721. doi: 10.1128/jvi.35.3.710-721.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. MCCULLOCH E. A., SIMINOVITCH L., TILL J. E. SPLEEN-COLONY FORMATION IN ANEMIC MICE OF GENOTYPE WW. Science. 1964 May 15;144(3620):844–846. doi: 10.1126/science.144.3620.844. [DOI] [PubMed] [Google Scholar]
  12. MacDonald M. E., Mak T. W., Bernstein A. Erythroleukemia induction by replication-competent type C viruses cloned from the anemia- and polycythemia-inducing isolates of Friend leukemia virus. J Exp Med. 1980 Jun 1;151(6):1493–1503. doi: 10.1084/jem.151.6.1493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Mager D. L., Mak T. W., Bernstein A. Quantitative colony method for tumorigenic cells transformed by two distinct strains of Friend leukemia virus. Proc Natl Acad Sci U S A. 1981 Mar;78(3):1703–1707. doi: 10.1073/pnas.78.3.1703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mager D., MacDonald M. E., Robson I. B., Mak T. W., Bernstein A. Clonal analysis of the late stages of erythroleukemia induced by two distinct strains of Friend leukemia virus. Mol Cell Biol. 1981 Aug;1(8):721–730. doi: 10.1128/mcb.1.8.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mager D., Mak T. W., Bernstein A. Friend leukaemia virus-transformed cells, unlike normal stem cells, form spleen colonies in Sl/sld mice. Nature. 1980 Dec 11;288(5791):592–594. doi: 10.1038/288592a0. [DOI] [PubMed] [Google Scholar]
  16. Mak T. W., Axelrad A. A., Bernstein A. Fv-2 locus controls expression of Friend spleen focus-forming virus-specific sequences in normal and infected mice. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5809–5812. doi: 10.1073/pnas.76.11.5809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mak T. W., Gamble C. L., MacDonald M. E., Bernstein A. Host control of sequences specific to Friend erythroleukemia virus in normal and leukemic mice. Cold Spring Harb Symp Quant Biol. 1980;44(Pt 2):893–899. doi: 10.1101/sqb.1980.044.01.096. [DOI] [PubMed] [Google Scholar]
  18. McCool D., Mak T. W., Bernstein A. Cellular regulation in Friend virus induced erythroleukemia. Studies with anemic mice of genotype Sl/Sld. J Exp Med. 1979 Apr 1;149(4):837–846. doi: 10.1084/jem.149.4.837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. McCulloch E. A., Siminovitch L., Till J. E., Russell E. S., Bernstein S. E. The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype Sl-Sld. Blood. 1965 Oct;26(4):399–410. [PubMed] [Google Scholar]
  20. Mirand E. A. Murine viral-induced polycyhemia. Ann N Y Acad Sci. 1968 Mar 29;149(1):486–496. doi: 10.1111/j.1749-6632.1968.tb15187.x. [DOI] [PubMed] [Google Scholar]
  21. Niho Y., Shibuya T., Mak T. W. Modulation of erythropoiesis by the helper-independent Friend leukemia virus F-MuLV. J Exp Med. 1982 Jul 1;156(1):146–158. doi: 10.1084/jem.156.1.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. ODAKA T., EDAKA T., YAMAMOTTO T. Inheritance of susceptibility to Friend mouse leukemia virus. Jpn J Exp Med. 1962 Oct;32:405–413. [PubMed] [Google Scholar]
  23. Odaka T., Ikeda H. Genetic resistance to Friend leukemia virus in mice: masking of Fv-2 phenotype by an epistatic gene, Fv-4. Jpn J Exp Med. 1977 Dec;47(6):515–521. [PubMed] [Google Scholar]
  24. Oliff A., Ruscetti S., Douglass E. C., Scolnick E. Isolation of transplantable erythroleukemia cells from mice infected with helper-independent Friend murine leukemia virus. Blood. 1981 Aug;58(2):244–254. [PubMed] [Google Scholar]
  25. Ostertag W., Melderis H., Steinheider G., Kluge N., Dube S. Synthesis of mouse haemoglobin and globin mRNA in leukaemic cell cultures. Nat New Biol. 1972 Oct 25;239(95):231–234. doi: 10.1038/newbio239231a0. [DOI] [PubMed] [Google Scholar]
  26. Ostertag W., Melderis H., Steinheider G., Kluge N., Dube S. Synthesis of mouse haemoglobin and globin mRNA in leukaemic cell cultures. Nat New Biol. 1972 Oct 25;239(95):231–234. doi: 10.1038/newbio239231a0. [DOI] [PubMed] [Google Scholar]
  27. Rowe W. P., Humphrey J. B., Lilly F. A major genetic locus affecting resistance to infection with murine leukemia viruses. 3. Assignment of the Fv-1 locus to linkage group 8 of the mouse. J Exp Med. 1973 Mar 1;137(3):850–853. doi: 10.1084/jem.137.3.850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rowe W. P., Pugh W. E., Hartley J. W. Plaque assay techniques for murine leukemia viruses. Virology. 1970 Dec;42(4):1136–1139. doi: 10.1016/0042-6822(70)90362-4. [DOI] [PubMed] [Google Scholar]
  29. Russell E. S. Hereditary anemias of the mouse: a review for geneticists. Adv Genet. 1979;20:357–459. [PubMed] [Google Scholar]
  30. Sassa S., Takaku F., Nakao K. Regulation of erythropoiesis in the Friend leukemia mouse. Blood. 1968 Jun;31(6):758–765. [PubMed] [Google Scholar]
  31. Shibuya T., Mak T. W. A host gene controlling early anaemia or polycythaemia induced by Friend erythroleukaemia virus. Nature. 1982 Apr 8;296(5857):577–579. doi: 10.1038/296577a0. [DOI] [PubMed] [Google Scholar]
  32. Shibuya T., Mak T. W. Induction of erythroid tumorigenic colonies by Friend helper virus F-MuLV alone and isolation of a new class of friend erythroleukemic cells. J Cell Physiol Suppl. 1982;1:185–194. doi: 10.1002/jcp.1041130426. [DOI] [PubMed] [Google Scholar]
  33. Steeves R. A., Bennett M., Mirand E. A., Cudkowicz G. Genetic control by the W locus of susceptibility to (Friend) spleen focus-forming virus. Nature. 1968 Apr 27;218(5139):372–374. doi: 10.1038/218372a0. [DOI] [PubMed] [Google Scholar]
  34. Steeves R. A., Eckner R. J., Bennett M., Mirand E. A., Trudel P. J. Isolation and characterization of a lymphatic leukemia virus in the Friend virus complex. J Natl Cancer Inst. 1971 Jun;46(6):1209–1217. [PubMed] [Google Scholar]
  35. Steeves R., Lilly F. Interactions between host and viral genomes in mouse leukemia. Annu Rev Genet. 1977;11:277–296. doi: 10.1146/annurev.ge.11.120177.001425. [DOI] [PubMed] [Google Scholar]
  36. Suzuki S., Axelrad A. A. Fv-2 locus controls the proportion of erythropoietic progenitor cells (BFU-E) synthesizing DNA in normal mice. Cell. 1980 Jan;19(1):225–236. doi: 10.1016/0092-8674(80)90404-3. [DOI] [PubMed] [Google Scholar]
  37. Sveda M. M., Soeiro R. Host restriction of Friend leukemia virus: synthesis and integration of the provirus. Proc Natl Acad Sci U S A. 1976 Jul;73(7):2356–2360. doi: 10.1073/pnas.73.7.2356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tambourin P. E., Gallien-Lartigue O., Wendling F., Huaulme D. Erythrocyte production in mice infected by the polycythaemia-inducing Friend virus or by the anaemia-inducing Friedn virus. Br J Haematol. 1973 Apr;24(4):511–524. doi: 10.1111/j.1365-2141.1973.tb01677.x. [DOI] [PubMed] [Google Scholar]
  39. Wendling F., Moreau-Gachelin F., Tambourin P. Emergence of tumorigenic cells during the course of Friend virus leukemias. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3614–3618. doi: 10.1073/pnas.78.6.3614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Yamamoto Y., Gamble C. L., Clark S. P., Joyner A., Shibuya T., MacDonald M. E., Mager D., Bernstein A., Mak T. W. Clonal analysis of early and late stages of erythroleukemia induced by molecular clones of integrated spleen focus-forming virus. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6893–6897. doi: 10.1073/pnas.78.11.6893. [DOI] [PMC free article] [PubMed] [Google Scholar]

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