Abstract
The mechanism leading to the expanding population of maturing myeloid cells which characterises chronic myeloid leukemia (CML) remains obscure. Because of its ability to mimic the proliferative and cell survival functions of hematopoietic growth factors, we hypothesized that the oncogene activated in CML, BCR – ABL, might also influence differentiation. To test this hypothesis, we examined the effects of expressing BCR – ABL on the myeloid differentiation of murine M1 leukemic cells, which cease dividing and differentiate into macrophages in the presence of the cytokines leukemia inhibitory factor (LIF) or interleukin (IL)-6. We found that BCR – ABL induced macrophage differentiation in M1 cells, accompanied by increased expression of macrophage cell surface markers and the acquisition of phagocytic ability. Interestingly, clones of M1 cells which expressed BCR – ABL remained in cell cycle and were refractory to the growth inhibition and apoptosis induced by IL-6 or LIF in parental M1 cells. These cells also expressed inappropriately high levels of c-MYC mRNA for their degree of differentiation, which may have been important in maintaining cellular proliferation. These data suggest that BCR – ABL can stimulate both differentiation and proliferation and that these characterisitics may contribute to the phenotype observed in CML.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Afar DE, Goga A, McLaughlin J, Witte ON and Sawyers CL. . 1994 Science 264: 424–426.
Afar DE, McLaughlin J, Sherr CJ, Witte ON and Roussel MF. . 1995 Proc. Natl. Acad. Sci. USA 92: 9540–9544.
Aktas H, Cai H and Cooper GM. . 1997 Mol. Cell. Biol. 17: 3850–3857.
Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A and Pestell RG. . 1995 J. Biol. Chem. 270: 23589–23597.
Austyn JM and Gordon S. . 1981 Eur. J. Immunol. 11: 805–815.
Bruce AG, Hoggatt IH and Rose TM. . 1992 J. Immunol. 149: 1271–1275.
Cambier N, Chopra R, Strasser A, Metcalf D and Elefanty AG. . 1998 Oncogene 16: 335–348.
Clarke MF, Kukowska-Latallo JF, Westin E, Smith M and Prochownik EV. . 1988 Mol. Cell. Biol. 8: 884–892.
Clarkson BD, Strife A, Wisniewski D, Lambek C and Carpino N. . 1997 Leukemia 11: 1404–1428.
Cleveland JL, Dean M, Rosenberg N, Wang JYJ and Rapp UR. . 1989 Mol. Cell. Biol. 9: 5685–5695.
Coppola JA and Cole MD. . 1986 Nature 320: 760–763.
Cortez D, Kadlec L and Pendergast AM. . 1995 Mol. Cell. Biol. 15: 5531–41.
Cortez D, Reuther G and Pendergast AM. . 1997 Oncogene 15: 2333–2342.
Cortez D, Stoica G, Pierce JH and Pendergast AM. . 1996 Oncogene 13: 2589–2594.
Daley GQ and Baltimore D. . 1988 Proc. Natl. Acad. Sci. USA 85: 9312–9316.
Daley GQ, Van Etten RA and Baltimore D. . 1990 Science 247: 824–830.
Dexter TM, Garland J, Scott D, Scolnick E and Metcalf D. . 1980 J. Exp. Med. 152: 1036–1047.
Dmitrovsky E, Kuehl WM, Hollis GF, Kirsch IR, Bender TP and Segal S. . 1986 Nature 322: 748–750.
Elefanty AG, Robb L and Begley CG. . 1997 Molecular Haemopoiesis. Whetton AD (ed.). Ballière Tindall: London. pp. 589–614.
Elefanty AG and Cory S. . 1992a Blood 79: 1271–1281.
Elefanty AG and Cory S. . 1992b Mol. Cell. Biol. 12: 1755–1763.
Elefanty AG, Hariharan IK and Cory S. . 1990 EMBO J. 9: 1069–1078.
Fraser IP, Hughes D and Gordon S. . 1993 Nature 364: 343–346.
Gishizky ML and Witte ON. . 1992 Science 256: 836–839.
Groffen J and Heisterkamp N. . 1987 Chronic Myeloid Leukaemia. Goldman JM (ed.). Baillière Tindall: London. pp. 983–999.
Hariharan IK, Adams JM and Cory S. . 1988 Oncogene Res. 3: 387–399.
Hoffman-Liebermann B and Liebermann DA. . 1991 Mol. Cell. Biol. 11: 2375–2381.
Huang D, Cory S and Strasser A. . 1997 Oncogene 14: 405–414.
Kelliher MA, McLaughlin J, Witte ON and Rosenberg N. . 1990 Proc. Natl. Acad. Sci. USA 87: 6649–6653.
Kodama T, Freeman M, Rohrer L, Zabrecky J, Matsudaira P and Krieger M. . 1990 Nature 343: 531–535.
Laneuville P, Heisterkamp N and Groffen J. . 1991 Oncogene 6: 275–282.
Leone G, DeGregori J, Sears R, Jakoi L and Nevins JR. . 1997 Nature 387: 422–426.
Liebermann DA and Hoffman-Liebermann B. . 1989 Oncogene 4: 583–592.
McClinton D, Stafford J, Brents L, Bender TP and Kuehl WM. . 1990 Mol. Cell. Biol. 10: 705–710.
Metcalf D. . 1984 Clonal Culture of Hemopoietic Cells: Techniques and Applications. Elsevier, Amsterdam.
Metcalf D, Hilton DJ and Nicola N. . 1988 Leukemia 2: 216–221.
Munson PJ and Rodbard D. . 1980 Anal. Biochem. 107: 220–239.
Palacios R and Steinmetz M. . 1985 Cell 41: 727–734.
Peeper DS, Upton TM, Ladha MH, Neuman E, Zalvide J, Bernards R, DeCaprio JA and Ewen ME. . 1997 Nature 386: 177–181.
Prochownik EV and Kukowska J. . 1986 Nature 322: 848–851.
Resnitzky D and Kimchi A. . 1991 Cell Growth Differ. 2: 33–41.
Rohrer L, Freeman M, Kodama T, Penman M and Krieger M. . 1990 Nature 343: 570–572.
Sawyers CL, Callahan W and Witte ON. . 1992 Cell 70: 901–910.
Schiff-Maker L, Burns M, Konopka J, Clark S, Witte O and Rosenberg N. . 1986 J. Virol. 57: 1182–1186.
Selvakumaran M, Liebermann DA and Hoffman-Liebermann B. . 1992 Mol. Cell. Biol. 12: 2493–2500.
Shabo Y, Lotem J, Rubinstein M, Revel M, Clark SC, Wolf SF, Kamen R and Sachs L. . 1988 Blood 72: 2070–2073.
Sirard C, Laneuville P and Dick JE. . 1994 Blood 83: 1575–1585.
Skorski T, Nieborowska-Skorska M, Wlodarski P, Perrotti D, Martinez R, Wasik MA and Calabretta B. . 1996 Proc. Natl. Acad. Sci. USA 93: 13137–13142.
Smith A, Metcalf D and Nicola NA. . 1997 EMBO J. 16: 451–464.
Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn BA, Quelle FW, Silvennoinen O, Barbieri G, Pellegrini S, Ihle JN and Yancopoulos GD. . 1994 Science 263: 92–95.
Strasser A, Harris AW, Huang DC, Krammer PH and Cory S. . 1995 EMBO J. 14: 6136–6147.
Tanigawa T, Nicola N, McArthur GA, Strasser A and Begley CG. . 1995 Blood 85: 379–390.
Tauchi T and Broxymeyer HE. . 1995 Int. J. Hematol. 61: 105–112.
Unkeless JC. . 1979 J. Exp. Med. 150: 580–596.
Vairo G, Innes KM and Adams JM. . 1996 Oncogene 13: 1511–1519.
Waldman T, Lengauer C, Kinzler KW and Vogelstein B. . 1996 Nature 381: 713–716.
Yonish-Rouach E, Resnitzky D, Lotem J, Sachs LAK and Oren M. . 1991 Nature 352: 345–347.
Zafriri D, Argaman M, Canaani E and Kimchi A. . 1993 Proc. Natl. Acad. Sci. USA 90: 477–481.
Acknowledgements
We thank Dr C Scott for assistance with phagocytic assays and labelled-LDL uptake experiments. S Olding and D Berry provided expert assistance with the preparation of figures and Dr CG Begley critically read the manuscript. This work was supported in part by the Association pour la Recherche contre le Cancer (NC), the Carden Fellowship Fund (DM), an Australian Research Council Queen Elizabeth II fellowship and an AMRAD postdoctoral award (GV), the Australian Federal Government Cooperative Research Centres Program (YZ) and the Lions Special Fellowship of the AntiCancer Council of Victoria (AGE), the National Health and Medical Research Council, Canberra and a grant from the National Institutes of Health, CA22556 (DM).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cambier, N., Zhang, Y., Vairo, G. et al. Expression of BCR – ABL in M1 myeloid leukemia cells induces differentiation without arresting proliferation. Oncogene 18, 343–352 (1999). https://doi.org/10.1038/sj.onc.1202302
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1202302
Keywords
This article is cited by
-
Improving detection of differentially expressed gene sets by applying cluster enrichment analysis to Gene Ontology
BMC Bioinformatics (2009)
-
Establishment and phenotypic characterization of human U937 cells with inducible P210 BCR/ABL expression reveals upregulation of CEACAM1 (CD66a)
Leukemia (2004)
-
The proto-oncogene c-myc in hematopoietic development and leukemogenesis
Oncogene (2002)
-
Modeling Philadelphia chromosome positive leukemias
Oncogene (2001)
-
Molecular Biology of Chronic Myeloid Leukemia
International Journal of Hematology (2001)