Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Growth Factors, Cytokines and Signal Transduction

Identification of a genetic locus modulating splenomegaly induced by granulocyte colony-stimulating factor in mice

Leukemia volume 14, pages 657–661 (2000)Cite this article

Abstract

Clinically detectable splenomegaly and splenic rupture are uncommon but potentially life-threatening consequences of G-CSF administration. Increased spleen size in mice injected with G-CSF is a complex genetic trait amenable to investigation in experimental inter-strain crosses by quantitative trait analysis. A quantitative trait locus (QTL) with highly significant linkage (LOD 7.9) for splenomegaly was identified within a 22 centimorgan (cM) region on chromosome 1. Inheritance of a C57BL/6 haplotype in this region was associated with a greater spleen weight. The relevance of this locus was confirmed by analysing the responses of mice congenic for the distal 12 cM of this region (C57BL/6 and C57BL/6.SJL-Ptprca Pep3b). Consistent with the QTL effect, mice lacking C57BL/6 alleles in this region had reduced splenomegaly induced by G-CSF. Intriguingly, peripheral blood neutrophilia and progenitor cell mobilisation responses to G-CSF were also significantly influenced.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. To LB, Haylock DN, Simmons PJ, Juttner CA . The biology and clinical uses of blood stem cells Blood 1997 89: 2233–2258

    CAS  PubMed  Google Scholar 

  2. Grigg AP, Roberts AW, Raunow H, Houghton S, Layton JE, Boyd AW, McGrath KM, Maher D . Optimising dose and scheduling of filgrastim (granulocyte colony-stimulating factor) for mobilization and collection of peripheral blood progenitor cells in normal volunteers Blood 1995 86: 4437–4445

    CAS  PubMed  Google Scholar 

  3. Dreger P, Haferlach T, Eckstein V, Jacobs S, Suttorp M, Löffler H, Müller-Ruchholtz W, Schmitz N . G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: safety, kinetics of mobilization, and composition of the graft Br J Haematol 1994 87: 609–613

    Article  CAS  PubMed  Google Scholar 

  4. Lane TA, Law P, Maruyama M, Young D, Burgess J, Mullen M, Mealiffe M, Terstappen LWMM, Hardwick A, Moubayed M, Oldham F, Corringham RET, Ho AD . Harvesting and enrichment of hematopoietic progenitor cells mobilized into the peripheral blood of normal donors by granulocyte–macrophage colony-stimulating factor (GM-CSF) or G-CSF: potential role in allogeneic marrow transplantation Blood 1995 85: 275–282

    CAS  PubMed  Google Scholar 

  5. Tjnnfjord GE, Steen R, Evensen SA, Thorsby E, Egeland T . Characterization of CD34+ peripheral blood cells from health adults mobilized by recombinant human granulocyte colony-stimulating factor Blood 1994 84: 2795–2801

    Google Scholar 

  6. DeLuca E, Sheridan WP, Watson D, Szer J, Begley CG . Prior chemotherapy does not prevent effective mobilisation by G-CSF of peripheral blood progenitor cells Br J Cancer 1992 66: 893–899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baumann I, Testa NG, Lange C, DeWynter E, Luft T, Dexter TM, vanHoef MEHM, Howell A . Haemopoietic cells mobilised into the circulation by lenograstim as alternative to bone marrow for allogeneic transplants Lancet 1993 341: 369

    Article  CAS  PubMed  Google Scholar 

  8. Roberts AW, DeLuca E, Begley CG, Basser R, Grigg AP, Metcalf D . Broad inter-individual variations in circulating progenitor cell numbers induced by granulocyte colony-stimulating factor therapy Stem Cells 1995 13: 512–516

    Article  CAS  PubMed  Google Scholar 

  9. Welte K, Boxer LA . Sever chronic neutropenia: pathophysiology and therapy Semin Hematol 1997 34: 267–278

    CAS  PubMed  Google Scholar 

  10. Becker PS, Wagle M, Matous S, Swanson RS, Pihan G, Lowry PA, Stewart FM, Heard SO . Spontaneous splenic rupture following administration of granulocyte colony-stimulating factor (G-CSF): occurence in an allogeneic donor of peripheral blood stem cells Biol Blood Marrow Transplant 1997 3: 45–49

    CAS  PubMed  Google Scholar 

  11. Falzetti F, Aversa F, Minelli O, Tabilio A . Spontaneous rupture of spleen during peripheral blood stem-cell mobilisation in a healthy donor Lancet 1999 353: 555

    CAS  PubMed  Google Scholar 

  12. Pojda Z, Molineux G, Dexter TM . Hemopoietic effects of short-term in vivo treatment of mice with various doses of rhG-CSF Exp Hematol 1990 18: 27–31

    CAS  PubMed  Google Scholar 

  13. Bungart B, Loeffler M, Goris H, Dontje B, Diehl V, Nijhof W . Differential effects of recombinant human colony stimulating factor (rhG-CSF) on stem cells in marrow, spleen and peripheral blood in mice Br J Haematol 1990 76: 174–179

    Article  CAS  PubMed  Google Scholar 

  14. Roberts AW, Metcalf D . Granulocyte colony-stimulating factor induces selective elevations of progenitor cells in the peripheral blood of mice Exp Hematol 1994 22: 1156–1163

    CAS  PubMed  Google Scholar 

  15. Molineux G, Pojda Z, Dexter TM . A comparison of hematopoiesis in normal and splenectomized mice treated with granulocyte colony-stimulating factor Blood 1990 75: 563–569

    CAS  PubMed  Google Scholar 

  16. Roberts AW, Foote S, Alexander WS, Scott C, Robb L, Metcalf D . Genetic influences determining progenitor cell mobilization and leukocytosis induced by granulocyte colony-stimulating factor Blood 1997 89: 2736–2744

    CAS  PubMed  Google Scholar 

  17. Lander ES, Botstein D . Mapping mendelian factors underlying quantitative traits using RFLP linkage maps Genetics 1989 121: 185–199

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lander ES, Schork NJ . Genetic dissection of complex traits Science 1994 265: 2037–2048

    Article  CAS  PubMed  Google Scholar 

  19. Foote SJ, Burt RA, Baldwin TM, Presente A, Roberts AW, Laural YL, Lew AM, Marshall VM . Mouse loci for malaria-inducedmortality and the control of parasitaemia Nat Genet 1997 17: 380–381

    Article  CAS  PubMed  Google Scholar 

  20. Dietrich W, Katz H, Lincoln SE, Shin HS, Friedman J, Dracopoli NC, Lander ES . A genetic map of the mouse suitable for typing intraspecific crosses Genetics 1992 131: 423–447

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Dietrich WF, Miller J, Steen R, Merchant MA, Damron-Boles D, Husain Z, Dredge R, Daly MJ, Ingalls KA, O'Connor TJ, Evans CA, DeAngelis MM, Levinson DM, Kruglyak L, Goodman N, Copeland NG, Jenkins NA, Hawkins TL, Stein L, Page DC, Lander ES . A comprehensive genetic map of the mouse genome Nature 1996 380: 149–152

    Article  CAS  PubMed  Google Scholar 

  22. Lander ES, Green P, Abrahamson J, Barlow A, Daly MJ, Lincoln SE, Newburg L . MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations Genomics 1987 1: 174–181

    Article  CAS  PubMed  Google Scholar 

  23. Mouse Genome Database (MGD), Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, Maine. World Wide Web (URL: http://www.informatics.jax.org/) (retrieved January 1996)

  24. Lander ES, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247

    Article  CAS  PubMed  Google Scholar 

  25. Mouse Genome Database (MGD), Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, Maine. World Wide Web (URL: http://www.informatics.jax.org/) (retrieved September 1999)

  26. Müller-Sieburg CE, Riblet R . Genetic control of the frequency of hematopoietic stem cells in mice: mapping of a candidate locus to chromosome 1 J Exp Med 1996 183: 1141–1150

    Article  PubMed  Google Scholar 

  27. de Haan G, Van Zant G . Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene J Exp Med 1997 186: 529–536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. de Haan G, Nijhof W, Van Zant G . Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity Blood 1997 89: 1543–1550

    CAS  PubMed  Google Scholar 

  29. Peters SO, Kittler EL, Ramshaw HS, Quesenberry PJ . Ex vivo expansion of murine marrow cells with interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor leads to impaired engraftment in irradiated hosts Blood 1996 87: 30–37

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Yvette Laural, James Wagglen and Vikki Marshall for assistance with the PCR genotyping; to Sandra Mifsud and Ladina Di Rago for careful technical assistance; and to AMRAD (Melbourne, Australia) for donating G-CSF for injection into mice. This work was supported by the National Health and Medical Research Council of Australia, the Carden Fellowship Fund of the Anti-Cancer Council of Victoria, the Wellcome Trust, Chugai Pharmaceutical Co. Ltd, and Grant No. CA22556 from the National Institutes of Health, Bethesda.

Author information

Authors and Affiliations

  1. Division of Haematology and Cancer Research, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia

    AW Roberts, M Hasegawa & D Metcalf

  2. Genetics and Bioinformatics Group, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia

    SJ Foote

Authors
  1. AW Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Hasegawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Metcalf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. SJ Foote
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roberts, A., Hasegawa, M., Metcalf, D. et al. Identification of a genetic locus modulating splenomegaly induced by granulocyte colony-stimulating factor in mice. Leukemia 14, 657–661 (2000). https://doi.org/10.1038/sj.leu.2401735

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2401735

Keywords

This article is cited by

Search

Advanced search

Quick links