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

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 period...

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Veröffentlicht in:Oncogene 2000-11, Vol.19 (48), p.5487-5497
Hauptverfasser: PIERCE, Andrew, SPOONCER, Elaine, WOOLEY, Sarah, DIVE, Caroline, FRANCIS, Julia M, MIYAN, Jaleel, OWEN-LYNCH, P. Jane, DEXTER, T. Michael, WHETTON, Anthony D
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container_end_page 5497
container_issue 48
container_start_page 5487
container_title Oncogene
container_volume 19
creator PIERCE, Andrew
SPOONCER, Elaine
WOOLEY, Sarah
DIVE, Caroline
FRANCIS, Julia M
MIYAN, Jaleel
OWEN-LYNCH, P. Jane
DEXTER, T. Michael
WHETTON, Anthony D
description 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 p53null 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.
doi_str_mv 10.1038/sj.onc.1203940
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Jane</creatorcontrib><creatorcontrib>DEXTER, T. Michael</creatorcontrib><creatorcontrib>WHETTON, Anthony D</creatorcontrib><title>Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation</title><title>Oncogene</title><addtitle>Oncogene</addtitle><description>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. 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source MEDLINE; SpringerLink Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
subjects Abl gene
Animals
Apoptosis
BCR gene
BCR-ABL protein
Biological and medical sciences
Bone marrow
Cancer research
Cell differentiation
Cell Differentiation - physiology
Cell differentiation, maturation, development, hematopoiesis
Cell physiology
Cell surface
Chronic myeloid leukemia
Cytology
Flow cytometry
Fundamental and applied biological sciences. Psychology
Fusion protein
Fusion Proteins, bcr-abl - metabolism
Gene Silencing
Genes, p53
Growth factors
Hematologic and hematopoietic diseases
Hematology
Humans
Interleukin 3
Interleukin-3 - pharmacology
Kinases
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Leukocytes (granulocytic)
Leukocytes (neutrophilic)
Medical research
Medical sciences
Mice
Molecular and cellular biology
Myeloid Cells - cytology
Myeloid Cells - enzymology
Neutrophils
p53 Protein
Pathogenesis
Protein-tyrosine kinase
Protein-Tyrosine Kinases - metabolism
Proteins
Stem cells
Temperature
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - biosynthesis
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - physiology
title Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation
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