Skip to main content
PMC home page
Mediators of Inflammation logoLink to Mediators of Inflammation
. 2004 Jun;13(3):145–150. doi: 10.1080/09511920410001713574

Granulocyte colony-stimulating factor and leukemogenesis.

Lorena Lobo de Figueiredo 1, Rodrigo Siqueira de Abreu e Lima 1, Eduardo Magalhães Rego 1
PMCID: PMC1781560  PMID: 15223604

Abstract

The granulocyte colony-stimulating factor (G-CSF) plays an important role in normal granulopoiesis. Its functions are mediated by specific receptors on the surface of responsive cells and, upon ligand binding, several cytoplasmic tyrosine kinases are activated. The cytoplasmic region proximal to the membrane of the G-CSF receptor (G-CSF-R) transduces proliferative and survival signals, whereas the distal carboxy-terminal region transduces maturation signals and suppresses the receptor's proliferative signals. Mutations in the G-CSF-R gene resulting in truncation of the carboxy-terminal region have been detected in a subset of patients with severe congenital neutropenia who developed acute myelogenous leukemia (AML). In addition, the AML1-ETO fusion protein, expressed in leukemic cells harboring the t(8;21), disrupt the physiological function of transcription factors such as C/EBPalpha and C/EBPepsilon, which in turn deregulate G-CSF-R expression. The resulting high levels of G-CSF-R and G-CSF-dependent cell proliferation may be associated with pathogenesis of AML with t(8;21). Moreover, in vitro and in vivo studies demonstrated that G-CSF may act as a co-stimulus augmenting the response of PML-RARalpha acute promyelocytic leukemia cells to all-trans-retinoic acid treatment. Finally, in the PLZF-RARalpha acute promyelocytic leukemia transgenic model, G-CSF deficiency suppressed leukemia development. Altogether, these data suggest that the G-CSF signaling pathway may play a role in leukemogenesis.

Full Text

The Full Text of this article is available as a PDF (136.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aprikyan Andrew A. G., Kutyavin Tatyana, Stein Steven, Aprikian Pavel, Rodger Elin, Liles W. Conrad, Boxer Laurence A., Dale David C. Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia. Exp Hematol. 2003 May;31(5):372–381. doi: 10.1016/s0301-472x(03)00048-1. [DOI] [PubMed] [Google Scholar]
  2. Basu Sunanda, Dunn Ashley, Ward Alister. G-CSF: function and modes of action (Review). Int J Mol Med. 2002 Jul;10(1):3–10. [PubMed] [Google Scholar]
  3. Da Silva N., Meyer-Monard S., Menot M. L., Parrado A., Lebel A., Balitrand N., Fenaux P., Micléa J. M., Rousselot P., Degos L. Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO. Hematol J. 2000;1(5):316–328. doi: 10.1038/sj.thj.6200047. [DOI] [PubMed] [Google Scholar]
  4. Dombret H. Granulocytic colony-stimulating factors in the management of patients with acute myeloid leukemia. Hematol Cell Ther. 1996 Jul;38(3):231–240. doi: 10.1007/s00282-996-0231-5. [DOI] [PubMed] [Google Scholar]
  5. Ferrara Felicetto, Schiavone Ettore Mariano, Palmieri Salvatore, Mele Giuseppina, Pocali Barbara, Scalia Giulia, Morabito Paolo, Sebastio Lucia, Del Vecchio Luigi. Complete remission induced by G-CSF in a patient with acute myeloid leukemia with t(8;21)(q22;q22). Hematol J. 2003;4(3):218–221. doi: 10.1038/sj.thj.6200225. [DOI] [PubMed] [Google Scholar]
  6. Fukunaga R., Ishizaka-Ikeda E., Seto Y., Nagata S. Expression cloning of a receptor for murine granulocyte colony-stimulating factor. Cell. 1990 Apr 20;61(2):341–350. doi: 10.1016/0092-8674(90)90814-u. [DOI] [PubMed] [Google Scholar]
  7. Fukunaga R., Seto Y., Mizushima S., Nagata S. Three different mRNAs encoding human granulocyte colony-stimulating factor receptor. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8702–8706. doi: 10.1073/pnas.87.22.8702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Huang F., Zhao H. P., Gao X. Z., Dai M. M., Fan L. L. Recombinant human G-CSF and retinoic acid in synergistically inducing granulocyte differentiation of human promyelocytic leukemic cells. Chin Med J (Engl) 1992 Sep;105(9):707–712. [PubMed] [Google Scholar]
  9. Hunter M. G., Avalos B. R. Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival. Blood. 2000 Mar 15;95(6):2132–2137. [PubMed] [Google Scholar]
  10. Ilaria R. L., Jr, Hawley R. G., Van Etten R. A. Dominant negative mutants implicate STAT5 in myeloid cell proliferation and neutrophil differentiation. Blood. 1999 Jun 15;93(12):4154–4166. [PubMed] [Google Scholar]
  11. Jansen J. H., de Ridder M. C., Geertsma W. M., Erpelinck C. A., van Lom K., Smit E. M., Slater R., vd Reijden B. A., de Greef G. E., Sonneveld P. Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor. Blood. 1999 Jul 1;94(1):39–45. [PubMed] [Google Scholar]
  12. Lieschke G. J., Grail D., Hodgson G., Metcalf D., Stanley E., Cheers C., Fowler K. J., Basu S., Zhan Y. F., Dunn A. R. Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood. 1994 Sep 15;84(6):1737–1746. [PubMed] [Google Scholar]
  13. Löwenberg Bob, van Putten Wim, Theobald Matthias, Gmür Jurg, Verdonck Leo, Sonneveld Pieter, Fey Martin, Schouten Harry, de Greef Georgine, Ferrant Augustin. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med. 2003 Aug 21;349(8):743–752. doi: 10.1056/NEJMoa025406. [DOI] [PubMed] [Google Scholar]
  14. Metcalf D., Nicola N. A. Proliferative effects of purified granulocyte colony-stimulating factor (G-CSF) on normal mouse hemopoietic cells. J Cell Physiol. 1983 Aug;116(2):198–206. doi: 10.1002/jcp.1041160211. [DOI] [PubMed] [Google Scholar]
  15. Mitsui Tetsuo, Watanabe Sumiko, Taniguchi Yoshihiro, Hanada Sachiyo, Ebihara Yasuhiro, Sato Takeshi, Heike Toshio, Mitsuyama Masao, Nakahata Tatsutoshi, Tsuji Kohichiro. Impaired neutrophil maturation in truncated murine G-CSF receptor-transgenic mice. Blood. 2003 Apr 15;101(8):2990–2995. doi: 10.1182/blood.V101.8.2990. [DOI] [PubMed] [Google Scholar]
  16. Pabst T., Mueller B. U., Harakawa N., Schoch C., Haferlach T., Behre G., Hiddemann W., Zhang D. E., Tenen D. G. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001 Apr;7(4):444–451. doi: 10.1038/86515. [DOI] [PubMed] [Google Scholar]
  17. Platzer E., Welte K., Gabrilove J. L., Lu L., Harris P., Mertelsmann R., Moore M. A. Biological activities of a human pluripotent hemopoietic colony stimulating factor on normal and leukemic cells. J Exp Med. 1985 Dec 1;162(6):1788–1801. doi: 10.1084/jem.162.6.1788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Rego E. M., Pandolfi P. P. Analysis of the molecular genetics of acute promyelocytic leukemia in mouse models. Semin Hematol. 2001 Jan;38(1):54–70. doi: 10.1016/s0037-1963(01)90006-x. [DOI] [PubMed] [Google Scholar]
  19. Rego Eduardo M., Pandolfi Pier Paolo. Reciprocal products of chromosomal translocations in human cancer pathogenesis: key players or innocent bystanders? Trends Mol Med. 2002 Aug;8(8):396–405. doi: 10.1016/s1471-4914(02)02384-5. [DOI] [PubMed] [Google Scholar]
  20. Seymour J. F., Lieschke G. J., Grail D., Quilici C., Hodgson G., Dunn A. R. Mice lacking both granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. Blood. 1997 Oct 15;90(8):3037–3049. [PubMed] [Google Scholar]
  21. Shimizu K., Kitabayashi I., Kamada N., Abe T., Maseki N., Suzukawa K., Ohki M. AML1-MTG8 leukemic protein induces the expression of granulocyte colony-stimulating factor (G-CSF) receptor through the up-regulation of CCAAT/enhancer binding protein epsilon. Blood. 2000 Jul 1;96(1):288–296. [PubMed] [Google Scholar]
  22. Stanley E., Lieschke G. J., Grail D., Metcalf D., Hodgson G., Gall J. A., Maher D. W., Cebon J., Sinickas V., Dunn A. R. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5592–5596. doi: 10.1073/pnas.91.12.5592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tenen D. G., Hromas R., Licht J. D., Zhang D. E. Transcription factors, normal myeloid development, and leukemia. Blood. 1997 Jul 15;90(2):489–519. [PubMed] [Google Scholar]
  24. Tenen Daniel G. Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer. 2003 Feb;3(2):89–101. doi: 10.1038/nrc989. [DOI] [PubMed] [Google Scholar]
  25. Tidow N., Pilz C., Teichmann B., Müller-Brechlin A., Germeshausen M., Kasper B., Rauprich P., Sykora K. W., Welte K. Clinical relevance of point mutations in the cytoplasmic domain of the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. Blood. 1997 Apr 1;89(7):2369–2375. [PubMed] [Google Scholar]
  26. Ward A. C., Smith L., de Koning J. P., van Aesch Y., Touw I. P. Multiple signals mediate proliferation, differentiation, and survival from the granulocyte colony-stimulating factor receptor in myeloid 32D cells. J Biol Chem. 1999 May 21;274(21):14956–14962. doi: 10.1074/jbc.274.21.14956. [DOI] [PubMed] [Google Scholar]
  27. Watari K., Asano S., Shirafuji N., Kodo H., Ozawa K., Takaku F., Kamachi S. Serum granulocyte colony-stimulating factor levels in healthy volunteers and patients with various disorders as estimated by enzyme immunoassay. Blood. 1989 Jan;73(1):117–122. [PubMed] [Google Scholar]
  28. Wiktor-Jedrzejczak W., Bartocci A., Ferrante A. W., Jr, Ahmed-Ansari A., Sell K. W., Pollard J. W., Stanley E. R. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4828–4832. doi: 10.1073/pnas.87.12.4828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Zhang D. E., Zhang P., Wang N. D., Hetherington C. J., Darlington G. J., Tenen D. G. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):569–574. doi: 10.1073/pnas.94.2.569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. de Koning J. P., Schelen A. M., Dong F., van Buitenen C., Burgering B. M., Bos J. L., Löwenberg B., Touw I. P. Specific involvement of tyrosine 764 of human granulocyte colony-stimulating factor receptor in signal transduction mediated by p145/Shc/GRB2 or p90/GRB2 complexes. Blood. 1996 Jan 1;87(1):132–140. [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES