Abstract
Chronic myeloid leukaemia (CML), a hematopoietic stem cell disorder is characterized by the expression of BCR–ABL. To investigate the effects of BCR–ABL on multipotent hematopoietic cells, a temperature sensitive BCR–ABL tyrosine kinase was expressed in the cell line, FDCP-Mix. BCR–ABL mediated an increase in c-kit expression that correlated with an enhanced mitogenic response to SCF. This was not observed in the absence of Bcr–Abl kinase activity or presence of the BCR–ABL inhibitor STI571, which also inhibits c-kit. When cultured in a combination of SCF plus G-CSF the FDCP-Mix cells undergo neutrophilic differentiation over a 7–10 day period. When BCR–ABL was active there was a marked inhibition of cell maturation compared to control cells in which BCR–ABL was either inactive or not present. However, BCR–ABL did not block differentiation as the cells eventually undergo terminal maturation. These data argue that BCR–ABL is directly responsible for the enhanced response to SCF reported in CML progenitor cells. Furthermore, although the primary effect of STI571 is via direct inhibition of BCR–ABL, STI571 additionally reduces the enhanced response to SCF. Thus there are two sites of STI571 action of potential importance in Bcr–Abl expressing cells.
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
Agarwal R, Doren S, Hicks B, Dunbar CE . 1995 Blood 85: 1306–1312
Al-Taher A, Bashein A, Nolan T, Hollingsworth M, Brady G . 2000 Yeast 17: 201–210
Carpino N, Wisniewski D, Strife A, Marshak D, Kobayashi R, Stillman B, Clarkson B . 1997 Cell 88: 197–204
Clarkson B, Strife A . 1993 Leukemia 7: 1683–1721
Dai ZH, Quackenbush RC, Courtney KD, Grove M, Cortez D, Reuther GM, Pendergast AM . 1998 Genes Dev. 12: 1415–1424
Daley GQ, Van ER, Baltimore D . 1990 Science 247: 824–830
Darley RL, Burnett AK . 1999 Exp. Hematol. 27: 1599–1608
Eaves AC, Barnett MJ, Ponchio L, Cashman JD, Petzer A, Eaves CJ . 1998 Stem Cells 16: 77–83
Evans CA, Pierce A, Winter SA, Spooncer E, Heyworth CM, Whetton AD . 1999 Blood 94: 1504–1514
Galli SJ, Zsebo KM, Geissler EN . 1994 Adv. Immunol. 55: 1–96
Gishizky ML, Witte ON . 1992 Science 256: 836–839
Gotoh A, Broxmeyer HE . 1997 Curr. Opin. Hematol. 4: 3–11
Griffiths SD, Healy LE, Ford AM, Bennett CA, Voncken JW, Heisterkamp N, Groffen J, Greaves MF . 1992 Oncogene 7: 1391–1399
Hallek M, Danhaser-Riedl S, Herbst R, Warmuth M, Winkler A, Kolb HJ, Druker B, Griffin JD, Emmerich B, Ullrich A . 1996 Br. J. Haematol. 94: 5–
Heinrich M, Griffith D, Drucker B, Wait C, Ott K, Zigler A . 2000 Blood 96: 925–932
Heisterkamp N, Jenster G, ten HJ, Zovich D, Pattengale PK, Groffen J . 1990 Nature 344: 251–253
Heyworth CM, Dexter TM, On K, Whetton AD . 1990 Growth Factors 2: 197–211
Honda H, Fujii T, Takatoku M, Mano H, Witte ON, Yazaki Y, Hirai H . 1995 Blood 85: 2853–2861
Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C . 1999 PNAS 96: 12804–12809
Kelliher MA, McLaughlin J, Witte ON, Rosenberg N . 1990 Proc. Natl. Acad. Sci. USA 87: 6649–6653
Konopka JB, Watanabe SM, Witte ON . 1984 Cell 37: 1035–1042
Lewis ID, McDiarmid LA, Samels LM, To LB, Hughes TP . 1998 Blood 91: 630–640
Lugo TG, Pendergast AM, Muller AJ, Witte ON . 1990 Science 247: 1079–1082
Moore S, Haylock DN, Levesque JP, McDiarmid LA, Samels LM, To LB, Simmons PJ, Hughes TP . 1998 Blood 92: 2461–2470
Pierce A, Owen-Lynch PJ, Spooncer E, Dexter TM, Whetton AD . 1998a Oncogene 17: 667–672
Pierce A, Whetton AD, Owen-Lynch PJ, Tavernier E, Spooncer E, Dexter TM, Heyworth CM . 1998b J. Cell Sci. 111: 815–823
Pierce A, Woolley S, Dive C, Miyan J, Spooncer E, Dexter T, Owen-Lynch P, Whetton A . 2000 Oncogene 19: 5487–5497
Sawyers CL . 1993 Leuk. Lymph. 2: 101–103
Tsai S, Bartelmez S, Heyman R, Damm K, Evans R, Collins SJ . 1992 Genes Dev. 6: 2258–2269
Verfaille CM . 1998 Hematol. Oncol. Clin. NA 12: 1
Wang JYJ . 1992 Curr. Biol. 2: 70–72
Wisniewski D, Strife A, Berman E, Clarkson B . 1996 Leukemia 10: 229–237
Acknowledgements
We thank Sue Slack, Rachel Mottram and Sandra Winter for their assistance. This work was supported by the Leukaemia Research Fund. We also thank Dr E Buchdunger (Novartis) for providing STI571.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pierce, A., Spooncer, E., Ainsworth, S. et al. BCR–ABL alters the proliferation and differentiation response of multipotent hematopoietic cells to stem cell factor. Oncogene 21, 3068–3075 (2002). https://doi.org/10.1038/sj.onc.1205424
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205424
Keywords
This article is cited by
-
Expression of CCL9/MIP-1γ is repressed by BCR/ABL and its restoration suppresses in vivo leukemogenesis of 32D-BCR/ABL cells
Oncogene (2007)
-
Overexpression of HOXB4 confers a myelo-erythroid differentiation delay in vitro
Leukemia (2005)
-
Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies
Leukemia (2003)
-
Chronic myelogenous leukemia molecular signature
Oncogene (2003)