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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


Mazin Gh. Al-Asadi

Grace Brindle

Marcos Castellanos

Ken I. Mills

Nigel Russell

Monica Pallis


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 ?1 (TGF?1) 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.


Al-Asadi, M. G., Brindle, G., Castellanos, M., May, S., Mills, K. I., Russell, N., …Pallis, M. (2017). A molecular signature of dormancy in CD34+CD38- acute myeloid leukaemia cells. Oncotarget, 8(67), 111405-111418.

Journal Article Type Article
Acceptance Date Nov 14, 2017
Publication Date Nov 30, 2017
Deposit Date Jan 8, 2018
Publicly Available Date Jan 8, 2018
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 8
Issue 67
Pages 111405-111418
Keywords AML; dormancy; gene expression profiling
Public URL
Publisher URL[]=22808&path[]=72005


CSeedhouse_Oncotarget_dormancy_17.pdf (12.9 Mb)

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