Regulation of tissue factor expression in myeloid and monocytic leukaemia cells

Tissue factor (TF) is a transmembrane glycoprotein that initiates the blood coagulation cascade and is also involved in cell migration, tumour metastasis and angiogenesis. Pathologic expression of tissue factor by monocytes contributes to several thrombotic complications like acute coronary artery d...

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Main Author: Tenno, Taavo
Format: Doctoral Thesis
Language:English
Published: Uppsala universitet, Institutionen för medicinska vetenskaper 2001
Subjects:
Online Access:http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-618
http://nbn-resolving.de/urn:isbn:91-554-4966-2
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spelling ndltd-UPSALLA1-oai-DiVA.org-uu-6182013-01-08T13:05:25ZRegulation of tissue factor expression in myeloid and monocytic leukaemia cellsengTenno, TaavoUppsala universitet, Institutionen för medicinska vetenskaperUppsala : Acta Universitatis Upsaliensis2001Medical sciencestissue factorblood coagulationmonocytescell differentiationretinoic acidvitamin D3acute promyelocytic leukaemiaMEDICIN OCH VÅRDMEDICINEMEDICINTissue factor (TF) is a transmembrane glycoprotein that initiates the blood coagulation cascade and is also involved in cell migration, tumour metastasis and angiogenesis. Pathologic expression of tissue factor by monocytes contributes to several thrombotic complications like acute coronary artery disease and disseminated intravascular coagulation. The aim of this thesis was to investigate the clinically important pathologic expression of TF in myelo-monocytic leukaemia cells and reveal the cellular signals leading to the suppression of TF expression. The studies in this thesis indicate that TF is a marker of immature myelo-monocytic cells. Markedly higher levels of TF were expressed in immature myelo-monocytic cell lines compared to mature monocyte-like cells. Induction of terminal differentiation in immature cells resulted in down-regulation of TF expression, irrespective of the specific phenotypes induced by retinoic acid (RA) or vitamin D3 in monoblastic U-937 cells. TF suppression was also found independent of differentiation pathways, i.e. monocytic or granulocytic. The nuclear receptor activation requirements for transcriptional suppression of TF by retinoic acid (RA) were shown to differ between acute promyelocytic leukaemia (APL) NB4 and U-937 cells. In NB4 cells the binding of the agonist to the RA receptor (RAR)α alone is needed for down-regulation of TF, whereas ligand binding to both RARαand retinoic X receptor was necessary for efficient suppression of TF expression in U-937 cells. To analyse the transcriptional regulation of TF, stable NB4 and U-937 clones expressing the luciferase gene under the control of various 5' flanking regions of the TF gene were selected. Different promoter regions were found to control the basal TF transcriptional activity. Analysis of protein binding to the 140 bp promoter region, responsible for basal TF activity in NB4 cells, revealed binding of RFX-1. RA suppressed the promoter activity in NB4, but not in U-937 cells. The ectopic expression of the APL fusion proteins PML/RARα or PLZF/RARα in U-937 reporter clones were shown to confer sensitivity to RA-induced suppression of TF promoter activity. These results provide a more detailed picture of TF regulation in leukaemic and haematopoietic cells and may have a bearing on new clinical treatment strategies in APL and other leukaemias. Doctoral thesis, comprehensive summaryinfo:eu-repo/semantics/doctoralThesistexthttp://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-618urn:isbn:91-554-4966-2Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1011application/pdfinfo:eu-repo/semantics/openAccess
collection NDLTD
language English
format Doctoral Thesis
sources NDLTD
topic Medical sciences
tissue factor
blood coagulation
monocytes
cell differentiation
retinoic acid
vitamin D3
acute promyelocytic leukaemia
MEDICIN OCH VÅRD
MEDICINE
MEDICIN
spellingShingle Medical sciences
tissue factor
blood coagulation
monocytes
cell differentiation
retinoic acid
vitamin D3
acute promyelocytic leukaemia
MEDICIN OCH VÅRD
MEDICINE
MEDICIN
Tenno, Taavo
Regulation of tissue factor expression in myeloid and monocytic leukaemia cells
description Tissue factor (TF) is a transmembrane glycoprotein that initiates the blood coagulation cascade and is also involved in cell migration, tumour metastasis and angiogenesis. Pathologic expression of tissue factor by monocytes contributes to several thrombotic complications like acute coronary artery disease and disseminated intravascular coagulation. The aim of this thesis was to investigate the clinically important pathologic expression of TF in myelo-monocytic leukaemia cells and reveal the cellular signals leading to the suppression of TF expression. The studies in this thesis indicate that TF is a marker of immature myelo-monocytic cells. Markedly higher levels of TF were expressed in immature myelo-monocytic cell lines compared to mature monocyte-like cells. Induction of terminal differentiation in immature cells resulted in down-regulation of TF expression, irrespective of the specific phenotypes induced by retinoic acid (RA) or vitamin D3 in monoblastic U-937 cells. TF suppression was also found independent of differentiation pathways, i.e. monocytic or granulocytic. The nuclear receptor activation requirements for transcriptional suppression of TF by retinoic acid (RA) were shown to differ between acute promyelocytic leukaemia (APL) NB4 and U-937 cells. In NB4 cells the binding of the agonist to the RA receptor (RAR)α alone is needed for down-regulation of TF, whereas ligand binding to both RARαand retinoic X receptor was necessary for efficient suppression of TF expression in U-937 cells. To analyse the transcriptional regulation of TF, stable NB4 and U-937 clones expressing the luciferase gene under the control of various 5' flanking regions of the TF gene were selected. Different promoter regions were found to control the basal TF transcriptional activity. Analysis of protein binding to the 140 bp promoter region, responsible for basal TF activity in NB4 cells, revealed binding of RFX-1. RA suppressed the promoter activity in NB4, but not in U-937 cells. The ectopic expression of the APL fusion proteins PML/RARα or PLZF/RARα in U-937 reporter clones were shown to confer sensitivity to RA-induced suppression of TF promoter activity. These results provide a more detailed picture of TF regulation in leukaemic and haematopoietic cells and may have a bearing on new clinical treatment strategies in APL and other leukaemias.
author Tenno, Taavo
author_facet Tenno, Taavo
author_sort Tenno, Taavo
title Regulation of tissue factor expression in myeloid and monocytic leukaemia cells
title_short Regulation of tissue factor expression in myeloid and monocytic leukaemia cells
title_full Regulation of tissue factor expression in myeloid and monocytic leukaemia cells
title_fullStr Regulation of tissue factor expression in myeloid and monocytic leukaemia cells
title_full_unstemmed Regulation of tissue factor expression in myeloid and monocytic leukaemia cells
title_sort regulation of tissue factor expression in myeloid and monocytic leukaemia cells
publisher Uppsala universitet, Institutionen för medicinska vetenskaper
publishDate 2001
url http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-618
http://nbn-resolving.de/urn:isbn:91-554-4966-2
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