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Activity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia.

TitleActivity of a heptad of transcription factors is associated with stem cell programs and clinical outcome in acute myeloid leukemia.
Publication TypeJournal Article
Year of Publication2013
AuthorsDiffner E, Beck D, Gudgin E, Thoms JAI, Knezevic K, Pridans C, Foster S, Goode D, Lim WKhong, Boelen L, Metzeler KH, Micklem G, Bohlander SK, Buske C, Burnett A, Ottersbach K, Vassiliou GS, Olivier J, Wong JWH, Göttgens B, Huntly BJ, Pimanda JE
Date Published2013 Mar 21
KeywordsAdaptor Proteins, Signal Transducing, Animals, Basic Helix-Loop-Helix Transcription Factors, Cells, Cultured, Core Binding Factor Alpha 2 Subunit, Enhancer Elements, Genetic, GATA2 Transcription Factor, Gene Expression Regulation, Leukemic, Hematopoietic Stem Cells, Humans, K562 Cells, Leukemia, Myeloid, Acute, LIM Domain Proteins, Mice, Mice, Transgenic, Neoplasm Proteins, Neoplastic Stem Cells, Prognosis, Proto-Oncogene Protein c-fli-1, Proto-Oncogene Proteins, Trans-Activators, Transcription Factors, Transcriptional Activation

Aberrant transcriptional programs in combination with abnormal proliferative signaling drive leukemic transformation. These programs operate in normal hematopoiesis where they are involved in hematopoietic stem cell (HSC) proliferation and maintenance. Ets Related Gene (ERG) is a component of normal and leukemic stem cell signatures and high ERG expression is a risk factor for poor prognosis in acute myeloid leukemia (AML). However, mechanisms that underlie ERG expression in AML and how its expression relates to leukemic stemness are unknown. We report that ERG expression in AML is associated with activity of the ERG promoters and +85 stem cell enhancer and a heptad of transcription factors that combinatorially regulate genes in HSCs. Gene expression signatures derived from ERG promoter-stem cell enhancer and heptad activity are associated with clinical outcome when ERG expression alone fails. We also show that the heptad signature is associated with AMLs that lack somatic mutations in NPM1 and confers an adverse prognosis when associated with FLT3 mutations. Taken together, these results suggest that transcriptional regulators cooperate to establish or maintain primitive stem cell-like signatures in leukemic cells and that the underlying pattern of somatic mutations contributes to the development of these signatures and modulate their influence on clinical outcome.

Alternate JournalBlood
PubMed ID23327922
Grant List079249 / / Wellcome Trust / United Kingdom
095663 / / Wellcome Trust / United Kingdom
100140 / / Wellcome Trust / United Kingdom
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