¹Leukaemia Research Fund Cellular Development Unit, UMIST, Sackville Street, Manchester, M60 1QD, UK

²Department of Biomolecular Sciences, UMIST, Sackville Street, Manchester, M60 1QD, UK

³Cancer Research Campaign, Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital, NHS Trust, Manchester, M20 9BX, UK

⁴Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK

Correspondence to: E Spooncer, Cancer Research Campaign, Department of Experimental Haematology, Paterson Institute for Cancer Research, Christie Hospital, NHS Trust, Manchester, M20 9BX, UK

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-Abl 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. Oncogene (2000) 19, 5487-5497.

Bcr-Abl; p53; CML; differentiation; haemopoietic