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

作者：Diffner Eva; Beck Dominik; Gudgin Emma; Thoms Julie A I; Knezevic Kathy; Pridans Clare; Foster Sam; Goode Debbie; Weng Khong Lim; Boelen Lies; Metzeler Klaus H; Micklem Gos; Bohlander Stefan K; Buske Christian; Burnett Alan; Otter**ach Katrin; Vassiliou George S; Olivier Jake; Wong Jason W H; Goettgens Berthold; Huntly Brian J; Pimanda John E^*

来源：Blood, 2013, 121(12): 2289-2300.

DOI：10.1182/blood-2012-07-446120

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 185 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.

• 出版日期2013-3-21
• 单位河北医科大学