Leukaemic transformation is driven by aberrant transcriptional programs often in combination with abnormal proliferative signalling. These programs operate in normal hematopoiesis where they are involved in hematopoietic stem cell (HSC) proliferation and maintenance.  ERG is a component of normal and leukemic stem cell signatures and high ERG expression has been proposed as 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+85 stem cell enhancer (SCE) and a heptad of transcription factors that combinatorially regulate genes in normal HSCs.  Gene expression signatures derived from ERG+85 stem cell enhancer and heptad activity predict clinical outcome in a cytogenetically normal cohort of AML (CN-AML) patients when ERG expression alone fails.  The heptad signature is an independent risk factor for poor overall and event-free survival. There were no long-term survivors amongst patients with a heptad signature, FLT3 mutations and wild-type NPM1 pointing to a hitherto unappreciated link between aberrant signaling and transcriptional mediators of hematopoietic stem cell identity.  In two independent cohorts, the heptad signature was as closely associated with wild-type NPM1 AML as the HOX signature was with mutant NPM1 AML suggestive of a collective role for these transcription factors in mediating the leukemic signature in the former.  Taken together, these results show that key transcriptional regulators cooperate in establishing stem cell signatures in leukemic cells and that the underlying spectrum of somatic mutations contributes to the development of these signatures and modulate their influence on clinical outcome.