A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells

Dormant leukaemia initiating cells in the bone marrow niche are a crucial therapeutic target for total eradication of acute myeloid leukaemia. To study this cellular subset we created and validated an in vitro model employing the cell line TF-1a, treated with Transforming Growth Factor β1 (TGFβ1) an...

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Main Authors:	Al-Asadi, Mazin Gh., Brindle, Grace, Castellanos, Marcos, May, Sean, Mills, Ken I., Russell, Nigel, Seedhouse, Claire, Pallis, Monica
Format:	Article
Published:	Impact Journals 2017
Subjects:	AML; dormancy; gene expression profiling
Online Access:	https://eprints.nottingham.ac.uk/48721/

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author	Al-Asadi, Mazin Gh. Brindle, Grace Castellanos, Marcos May, Sean Mills, Ken I. Russell, Nigel Seedhouse, Claire Pallis, Monica
author_facet	Al-Asadi, Mazin Gh. Brindle, Grace Castellanos, Marcos May, Sean Mills, Ken I. Russell, Nigel Seedhouse, Claire Pallis, Monica
author_sort	Al-Asadi, Mazin Gh.
building	Nottingham Research Data Repository
collection	Online Access
description	Dormant leukaemia initiating cells in the bone marrow niche are a crucial therapeutic target for total eradication of acute myeloid leukaemia. To study this cellular subset we created and validated an in vitro model employing the cell line TF-1a, treated with Transforming Growth Factor β1 (TGFβ1) and a mammalian target of rapamycin inhibitor. The treated cells showed decreases in total RNA, Ki-67 and CD71, increased aldehyde dehydrogenase activity, forkhead box 03A (FOX03A) nuclear translocation and growth inhibition, with no evidence of apoptosis or differentiation. Using human genome gene expression profiling we identified a signature enriched for genes involved in adhesion, stemness/inhibition of differentiation and tumour suppression as well as canonical cell cycle regulation. The most upregulated gene was the osteopontin-coding gene SPP1. Dormant cells also demonstrated significantly upregulated beta 3 integrin (ITGB3) and CD44, as well as increased adhesion to their ligands vitronectin and hyaluronic acid as well as to bone marrow stromal cells. Immunocytochemistry of bone marrow biopsies of AML patients confirmed the positive expression of osteopontin in blasts near the para-trabecular bone marrow, whereas osteopontin was rarely detected in mononuclear cell isolates. Unsupervised hierarchical clustering of the dormancy gene signature in primary acute myeloid leukaemia samples from the Cancer Genome Atlas identified a cluster enriched for dormancy genes associated with poor overall survival.
first_indexed	2025-11-14T20:10:09Z
format	Article
id	nottingham-48721
institution	University of Nottingham Malaysia Campus
institution_category	Local University
last_indexed	2025-11-14T20:10:09Z
publishDate	2017
publisher	Impact Journals
recordtype	eprints
repository_type	Digital Repository
spelling	nottingham-487212020-05-04T19:19:41Z https://eprints.nottingham.ac.uk/48721/ A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells Al-Asadi, Mazin Gh. Brindle, Grace Castellanos, Marcos May, Sean Mills, Ken I. Russell, Nigel Seedhouse, Claire Pallis, Monica Dormant leukaemia initiating cells in the bone marrow niche are a crucial therapeutic target for total eradication of acute myeloid leukaemia. To study this cellular subset we created and validated an in vitro model employing the cell line TF-1a, treated with Transforming Growth Factor β1 (TGFβ1) and a mammalian target of rapamycin inhibitor. The treated cells showed decreases in total RNA, Ki-67 and CD71, increased aldehyde dehydrogenase activity, forkhead box 03A (FOX03A) nuclear translocation and growth inhibition, with no evidence of apoptosis or differentiation. Using human genome gene expression profiling we identified a signature enriched for genes involved in adhesion, stemness/inhibition of differentiation and tumour suppression as well as canonical cell cycle regulation. The most upregulated gene was the osteopontin-coding gene SPP1. Dormant cells also demonstrated significantly upregulated beta 3 integrin (ITGB3) and CD44, as well as increased adhesion to their ligands vitronectin and hyaluronic acid as well as to bone marrow stromal cells. Immunocytochemistry of bone marrow biopsies of AML patients confirmed the positive expression of osteopontin in blasts near the para-trabecular bone marrow, whereas osteopontin was rarely detected in mononuclear cell isolates. Unsupervised hierarchical clustering of the dormancy gene signature in primary acute myeloid leukaemia samples from the Cancer Genome Atlas identified a cluster enriched for dormancy genes associated with poor overall survival. Impact Journals 2017-11-30 Article PeerReviewed Al-Asadi, Mazin Gh., Brindle, Grace, Castellanos, Marcos, May, Sean, Mills, Ken I., Russell, Nigel, Seedhouse, Claire and Pallis, Monica (2017) A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells. Oncotarget, 8 (67). pp. 111405-111418. ISSN 1949-2553 AML; dormancy; gene expression profiling http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22808&path[]=72005 doi:10.18632/oncotarget.22808 doi:10.18632/oncotarget.22808
spellingShingle	AML; dormancy; gene expression profiling Al-Asadi, Mazin Gh. Brindle, Grace Castellanos, Marcos May, Sean Mills, Ken I. Russell, Nigel Seedhouse, Claire Pallis, Monica A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells
title	A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells
title_full	A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells
title_fullStr	A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells
title_full_unstemmed	A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells
title_short	A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells
title_sort	molecular signature of dormancy in cd34+cd38- acute myeloid leukaemia cells
topic	AML; dormancy; gene expression profiling
url	https://eprints.nottingham.ac.uk/48721/ https://eprints.nottingham.ac.uk/48721/ https://eprints.nottingham.ac.uk/48721/

A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells

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