The majority of patients with acute myeloid leukemia (AML) still die of their 
disease, and novel therapeutic concepts are needed. Timely expression of the 
hematopoietic master regulator PU.1 is crucial for normal development of myeloid 
and lymphoid cells. Targeted disruption of an upstream regulatory element (URE) 
located several kb upstream in the PU.1 promoter decreases PU.1 expression 
thereby inducing AML in mice. In addition, suppression of PU.1 has been observed 
in specific subtypes of human AML. Here, we identified nuclear factor-kappaB 
(NF-kappaB) to activate PU.1 expression through a novel site within the URE. We 
found sequence variations of this particular NF-kappaB site in 4 of 120 AML 
patients. These variant NF-kappaB sequences failed to mediate activation of 
PU.1. Moreover, the synergistic activation of PU.1 together with CEBPB through 
these variant sequences was also lost. Finally, AML patients with such variant 
sequences had suppressed PU.1 mRNA expression. This study suggests that changes 
of a single base pair in a distal element critically affect the regulation of 
the tumor suppressor gene PU.1 thereby contributing to the development of AML.