Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation

Andrew Pierce, Elaine Spooncer, Sarah Wooley, Caroline Dive, Julia M. Francis, Jaleel Miyan, P. Jane Owen-Lynch, T. Michael Dexter, Anthony D. Whetton

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Chronic myeloid leukaemia is a haemopoietic stem cell disorder, the hallmark of which is the expression of the Bcr-Abl Protein Tyrosine Kinase (PTK). We have previously reported that activation of a temperature sensitive Bcr-AbI PTK in the multipotent haemopoietic cell line FDCP-Mix for short periods resulted in subtle changes including, a transient suppression of apoptosis and no inhibition of differentiation. In contrast, activation of the Bcr-Abl PTK for 12 weeks results in cells that display a delay in differentiation at the early granulocyte stage. Flow cytometric analysis also indicates that the expression of cell surface differentiation markers and nuclear morphology are uncoupled. Furthermore, a significant number of the mature neutrophils display abnormal morphological features. Prolonged exposure to Bcr-Abl PTK results in interleukin-3 independent growth and decreased p53 protein levels. FDCP-Mix cells expressing a dominant negative p53 and p53(null) FDCP-Mix cells demonstrate that the reduction in p53 is causally related to the delay in development. Returning the cells to the restrictive temperature restores the p53 protein levels, the growth factor dependence and largely relieves the effects on development. We conclude that prolonged Bcr-Abl PTK activity within multipotent cells results in a reduction of p53 that drives a delayed and abnormal differentiation.

Original languageEnglish
Pages (from-to)5487-5497
Number of pages11
JournalOncogene
Volume19
Issue number48
DOIs
Publication statusPublished - 16 Nov 2000
Externally publishedYes

Fingerprint

bcr-abl Fusion Proteins
Protein-Tyrosine Kinases
Proteins
Temperature
Interleukin-3
Differentiation Antigens
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Granulocytes
Cell Differentiation
Intercellular Signaling Peptides and Proteins
Neutrophils
Stem Cells
Apoptosis
Cell Line
Growth

Cite this

Pierce, A., Spooncer, E., Wooley, S., Dive, C., Francis, J. M., Miyan, J., ... Whetton, A. D. (2000). Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation. Oncogene, 19(48), 5487-5497. https://doi.org/10.1038/sj.onc.1203940
Pierce, Andrew ; Spooncer, Elaine ; Wooley, Sarah ; Dive, Caroline ; Francis, Julia M. ; Miyan, Jaleel ; Owen-Lynch, P. Jane ; Dexter, T. Michael ; Whetton, Anthony D. / Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation. In: Oncogene. 2000 ; Vol. 19, No. 48. pp. 5487-5497.
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Pierce, A, Spooncer, E, Wooley, S, Dive, C, Francis, JM, Miyan, J, Owen-Lynch, PJ, Dexter, TM & Whetton, AD 2000, 'Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation', Oncogene, vol. 19, no. 48, pp. 5487-5497. https://doi.org/10.1038/sj.onc.1203940

Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation. / Pierce, Andrew; Spooncer, Elaine; Wooley, Sarah; Dive, Caroline; Francis, Julia M.; Miyan, Jaleel; Owen-Lynch, P. Jane; Dexter, T. Michael; Whetton, Anthony D.

In: Oncogene, Vol. 19, No. 48, 16.11.2000, p. 5487-5497.

Research output: Contribution to journalArticle

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T1 - Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation

AU - Pierce, Andrew

AU - Spooncer, Elaine

AU - Wooley, Sarah

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AU - Francis, Julia M.

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AU - Dexter, T. Michael

AU - Whetton, Anthony D.

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