PU.1 is regulated by NF-kappaB through a novel binding site in a 17 kb upstream enhancer element.
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.
Bonadies
N
N
Department of Internal Medicine and Clinical Research, University Hospital Bern, University of Bern, Bern, Switzerland.
Neururer
Ch
Ch
Steege
A
A
Vallabhapurapu
S
S
Pabst
T
T
Mueller
B U
BU
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D019556:COS Cells; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000099232:Proto-Oncogene Protein Spi-1
D022782:CCAAT-Enhancer-Binding Protein-beta; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C545012:CEBPB protein, human