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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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 ; DEXTER, T. Michael ; WHETTON, Anthony D</creator><creatorcontrib>PIERCE, Andrew ; SPOONCER, Elaine ; WOOLEY, Sarah ; DIVE, Caroline ; FRANCIS, Julia M ; MIYAN, Jaleel ; OWEN-LYNCH, P. Jane ; DEXTER, T. Michael ; WHETTON, Anthony D</creatorcontrib><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.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1203940</identifier><identifier>PMID: 11114726</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>Basingstoke: Nature Publishing</publisher><subject>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</subject><ispartof>Oncogene, 2000-11, Vol.19 (48), p.5487-5497</ispartof><rights>2001 INIST-CNRS</rights><rights>COPYRIGHT 2000 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Nov 16, 2000</rights><rights>Macmillan Publishers Limited 2000.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c512t-3a273d7436c2944cfa22af4a660c878c5ff52de7a06a9c91b2cb01ea9ed70b063</citedby><cites>FETCH-LOGICAL-c512t-3a273d7436c2944cfa22af4a660c878c5ff52de7a06a9c91b2cb01ea9ed70b063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=844453$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11114726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PIERCE, Andrew</creatorcontrib><creatorcontrib>SPOONCER, Elaine</creatorcontrib><creatorcontrib>WOOLEY, Sarah</creatorcontrib><creatorcontrib>DIVE, Caroline</creatorcontrib><creatorcontrib>FRANCIS, Julia M</creatorcontrib><creatorcontrib>MIYAN, Jaleel</creatorcontrib><creatorcontrib>OWEN-LYNCH, P. 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. 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.</description><subject>Abl gene</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>BCR gene</subject><subject>BCR-ABL protein</subject><subject>Biological and medical sciences</subject><subject>Bone marrow</subject><subject>Cancer research</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - physiology</subject><subject>Cell differentiation, maturation, development, hematopoiesis</subject><subject>Cell physiology</subject><subject>Cell surface</subject><subject>Chronic myeloid leukemia</subject><subject>Cytology</subject><subject>Flow cytometry</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fusion protein</subject><subject>Fusion Proteins, bcr-abl - metabolism</subject><subject>Gene Silencing</subject><subject>Genes, p53</subject><subject>Growth factors</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hematology</subject><subject>Humans</subject><subject>Interleukin 3</subject><subject>Interleukin-3 - pharmacology</subject><subject>Kinases</subject><subject>Leukemia</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology</subject><subject>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Leukocytes (granulocytic)</subject><subject>Leukocytes (neutrophilic)</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Molecular and cellular biology</subject><subject>Myeloid Cells - cytology</subject><subject>Myeloid Cells - enzymology</subject><subject>Neutrophils</subject><subject>p53 Protein</subject><subject>Pathogenesis</subject><subject>Protein-tyrosine kinase</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Proteins</subject><subject>Stem cells</subject><subject>Temperature</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Suppressor Protein p53 - biosynthesis</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - physiology</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkkuPFCEUhYnROD2jW5eGaDK7ankVNMt24iuZxI2uyS0KlLYKWqA0_e-ltWMbM0ZYkNx85z64B6EnlKwp4ZsXZbdO0a4pI1wLcg-tqFCy63st7qMV0T3pNOPsAl2WsiOEKE3YQ3RB2xGKyRX6_tLmbjtMeJ9TdSHiesiphOjwlxChOAy2hm-hHnCI42JdwYCnVApOHu97fpZ9hopnNwaoP5nRTXDU4PngphRGPAbvXXaxNiKk-Ag98DAV9_j0XqGPr199uHnb3b5_8-5me9vZnrLacWCKj0pwaZkWwnpgDLwAKYndqI3tve_Z6BQQCdpqOjA7EOpAu1GRgUh-ha5_5W2Nfl1cqWYOxbppgujSUoxiQveUiP-CVKn2s1I18Plf4C4tObYhDJOCcsYUY4169k-qjUS5EJtzqk8wOROiTzWDPdY1W0aIoJKSY8H1HVS7o5uDTdH50OJ3CWxbZcnOm30OM-SDocQcXWPKzjTXmJNrmuDpqdllaDs84yeb_DEzFAuTzxBtKL-5jRCi5_wHlCvIdA</recordid><startdate>20001116</startdate><enddate>20001116</enddate><creator>PIERCE, Andrew</creator><creator>SPOONCER, Elaine</creator><creator>WOOLEY, Sarah</creator><creator>DIVE, Caroline</creator><creator>FRANCIS, Julia M</creator><creator>MIYAN, Jaleel</creator><creator>OWEN-LYNCH, P. 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Jane ; DEXTER, T. Michael ; WHETTON, Anthony D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c512t-3a273d7436c2944cfa22af4a660c878c5ff52de7a06a9c91b2cb01ea9ed70b063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Abl gene</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>BCR gene</topic><topic>BCR-ABL protein</topic><topic>Biological and medical sciences</topic><topic>Bone marrow</topic><topic>Cancer research</topic><topic>Cell differentiation</topic><topic>Cell Differentiation - physiology</topic><topic>Cell differentiation, maturation, development, hematopoiesis</topic><topic>Cell physiology</topic><topic>Cell surface</topic><topic>Chronic myeloid leukemia</topic><topic>Cytology</topic><topic>Flow cytometry</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fusion protein</topic><topic>Fusion Proteins, bcr-abl - metabolism</topic><topic>Gene Silencing</topic><topic>Genes, p53</topic><topic>Growth factors</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Hematology</topic><topic>Humans</topic><topic>Interleukin 3</topic><topic>Interleukin-3 - pharmacology</topic><topic>Kinases</topic><topic>Leukemia</topic><topic>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology</topic><topic>Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Leukocytes (granulocytic)</topic><topic>Leukocytes (neutrophilic)</topic><topic>Medical research</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Molecular and cellular biology</topic><topic>Myeloid Cells - cytology</topic><topic>Myeloid Cells - enzymology</topic><topic>Neutrophils</topic><topic>p53 Protein</topic><topic>Pathogenesis</topic><topic>Protein-tyrosine kinase</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Proteins</topic><topic>Stem cells</topic><topic>Temperature</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Suppressor Protein p53 - biosynthesis</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PIERCE, Andrew</creatorcontrib><creatorcontrib>SPOONCER, Elaine</creatorcontrib><creatorcontrib>WOOLEY, Sarah</creatorcontrib><creatorcontrib>DIVE, Caroline</creatorcontrib><creatorcontrib>FRANCIS, Julia M</creatorcontrib><creatorcontrib>MIYAN, Jaleel</creatorcontrib><creatorcontrib>OWEN-LYNCH, P. 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Jane</au><au>DEXTER, T. Michael</au><au>WHETTON, Anthony D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bcr-Abl protein tyrosine kinase activity induces a loss of p53 protein that mediates a delay in myeloid differentiation</atitle><jtitle>Oncogene</jtitle><addtitle>Oncogene</addtitle><date>2000-11-16</date><risdate>2000</risdate><volume>19</volume><issue>48</issue><spage>5487</spage><epage>5497</epage><pages>5487-5497</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><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-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.</abstract><cop>Basingstoke</cop><pub>Nature Publishing</pub><pmid>11114726</pmid><doi>10.1038/sj.onc.1203940</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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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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