Abl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha.

2.50
Hdl Handle:
http://hdl.handle.net/10541/93094
Title:
Abl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha.
Authors:
Wark, G; Heyworth, Clare M; Spooncer, Elaine; Czaplewski, L; Francis, Julia M; Dexter, T Michael; Whetton, Anthony D
Abstract:
The clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haemopoietic progenitor cells, are resistant to the growth inhibitory effects of the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha). CML is also relatively resistant to chemotherapy and the disease is difficult to cure using conventional therapeutic routes. CML is associated with increased abl oncogene protein tyrosine kinase (PTK) activity. Here, we have tested the hypothesis that these aberrant responses to MIP-1alpha and the relative resistance to chemotherapy are directly related to this increased abl PTK activity in primitive haemopoietic cells. To do this we have expressed a temperature sensitive abl PTK in a growth factor dependent, multipotent stem cell line (FDCP-Mix) in which growth is normally suppressed by MIP-1alpha. In FDCP-Mix cells expressing the ts v-abl PTK and grown at the restrictive temperature for PTK activity the cells were relatively sensitive to cytotoxic agents such as cytosine arabinoside and 5-fluorouracil but MIP-1alpha could induce growth inhibition and confer some degree of protection from these agents. At the permissive temperature for abl PTK, the cells were relatively resistant to cytotoxic drugs and MIP-1alpha treatment neither induced growth inhibition nor protected the cells from cytotoxic drug induced cell death. This lack of response to MIP-1alpha was not due to receptor down modulation as neither the affinity nor the number of 125I-MIP-1alpha binding sites was altered by activating Abl PTK. However, MIP-1alpha mediated increases in cytosolic Ca2+ levels were abrogated by switching cells to the permissive temperature for Abl PTK activity. These data suggest that the relative resistance of CML progenitor cells to therapeutic drugs and the lack of response to MIP-1alpha occurs as a direct consequence of abl PTK activity and involves desensitisation of signal transduction events stimulated by MIP-1alpha receptors. Thus one contributory mechanism to transformation of primitive haemopoietic cells is abrogation of response to a growth inhibitor.
Affiliation:
Leukaemia Research Fund Cellular Development Unit, UMIST, Manchester, UK.
Citation:
Abl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha. 1998, 16 (10):1319-24 Oncogene
Journal:
Oncogene
Issue Date:
12-Mar-1998
URI:
http://hdl.handle.net/10541/93094
DOI:
10.1038/sj.onc.1201914
PubMed ID:
9546433
Type:
Article
Language:
en
ISSN:
0950-9232
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorWark, Gen
dc.contributor.authorHeyworth, Clare Men
dc.contributor.authorSpooncer, Elaineen
dc.contributor.authorCzaplewski, Len
dc.contributor.authorFrancis, Julia Men
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorWhetton, Anthony Den
dc.date.accessioned2010-02-25T16:15:05Z-
dc.date.available2010-02-25T16:15:05Z-
dc.date.issued1998-03-12-
dc.identifier.citationAbl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha. 1998, 16 (10):1319-24 Oncogeneen
dc.identifier.issn0950-9232-
dc.identifier.pmid9546433-
dc.identifier.doi10.1038/sj.onc.1201914-
dc.identifier.urihttp://hdl.handle.net/10541/93094-
dc.description.abstractThe clonogenic cells of chronic myeloid leukaemia (CML), unlike normal haemopoietic progenitor cells, are resistant to the growth inhibitory effects of the chemokine macrophage inflammatory protein-1 alpha (MIP-1alpha). CML is also relatively resistant to chemotherapy and the disease is difficult to cure using conventional therapeutic routes. CML is associated with increased abl oncogene protein tyrosine kinase (PTK) activity. Here, we have tested the hypothesis that these aberrant responses to MIP-1alpha and the relative resistance to chemotherapy are directly related to this increased abl PTK activity in primitive haemopoietic cells. To do this we have expressed a temperature sensitive abl PTK in a growth factor dependent, multipotent stem cell line (FDCP-Mix) in which growth is normally suppressed by MIP-1alpha. In FDCP-Mix cells expressing the ts v-abl PTK and grown at the restrictive temperature for PTK activity the cells were relatively sensitive to cytotoxic agents such as cytosine arabinoside and 5-fluorouracil but MIP-1alpha could induce growth inhibition and confer some degree of protection from these agents. At the permissive temperature for abl PTK, the cells were relatively resistant to cytotoxic drugs and MIP-1alpha treatment neither induced growth inhibition nor protected the cells from cytotoxic drug induced cell death. This lack of response to MIP-1alpha was not due to receptor down modulation as neither the affinity nor the number of 125I-MIP-1alpha binding sites was altered by activating Abl PTK. However, MIP-1alpha mediated increases in cytosolic Ca2+ levels were abrogated by switching cells to the permissive temperature for Abl PTK activity. These data suggest that the relative resistance of CML progenitor cells to therapeutic drugs and the lack of response to MIP-1alpha occurs as a direct consequence of abl PTK activity and involves desensitisation of signal transduction events stimulated by MIP-1alpha receptors. Thus one contributory mechanism to transformation of primitive haemopoietic cells is abrogation of response to a growth inhibitor.en
dc.language.isoenen
dc.subjectHaematopoietic Stem Cellsen
dc.subjectLeukaemiaen
dc.subject.meshCalcium-
dc.subject.meshChemokine CCL3-
dc.subject.meshChemokine CCL4-
dc.subject.meshDNA Replication-
dc.subject.meshGrowth Inhibitors-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshHumans-
dc.subject.meshInterleukin-3-
dc.subject.meshKinetics-
dc.subject.meshLeukemia, Myelogenous, Chronic, BCR-ABL Positive-
dc.subject.meshMacrophage Inflammatory Proteins-
dc.subject.meshProtein-Tyrosine Kinases-
dc.subject.meshProto-Oncogene Proteins c-abl-
dc.subject.meshRecombinant Proteins-
dc.subject.meshThymidine-
dc.subject.meshTransfection-
dc.titleAbl protein kinase abrogates the response of multipotent haemopoietic cells to the growth inhibitor macrophage inflammatory protein-1 alpha.en
dc.typeArticleen
dc.contributor.departmentLeukaemia Research Fund Cellular Development Unit, UMIST, Manchester, UK.en
dc.identifier.journalOncogeneen
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