Heterozygous PU.1 mutations are associated with acute myeloid leukemia.
The transcription factor PU.1 is required for normal blood cell development. PU.1 regulates the expression of a number of crucial myeloid genes, such as the macrophage colony-stimulating factor (M-CSF) receptor, the granulocyte colony-stimulating factor (G-CSF) receptor, and the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor. Myeloid cells derived from PU.1(-/-) mice are blocked at the earliest stage of myeloid differentiation, similar to the blast cells that are the hallmark of human acute myeloid leukemia (AML). These facts led us to hypothesize that molecular abnormalities involving the PU.1 gene could contribute to the development of AML. We identified 10 mutant alleles of the PU.1 gene in 9 of 126 AML patients. The PU.1 mutations comprised 5 deletions affecting the DNA-binding domain, and 5 point mutations in 1) the DNA-binding domain (2 patients), 2) the PEST domain (2 patients), and 3) the transactivation domain (one patient). DNA binding to and transactivation of the M-CSF receptor promoter, a direct PU.1 target gene, were deficient in the 7 PU.1 mutants that affected the DNA-binding domain. In addition, these mutations decreased the ability of PU.1 to synergize with PU.1-interacting proteins such as AML1 or c-Jun in the activation of PU.1 target genes. This is the first report of mutations in the PU.1 gene in human neoplasia and suggests that disruption of PU.1 function contributes to the block in differentiation found in AML patients.
Mueller
Beatrice U
BU
Harvard Institutes of Medicine, Harvard Medical School, Boston, MA, USA.
Pabst
Thomas
T
Osato
Motomi
M
Asou
Norio
N
Johansen
Lisa M
LM
Minden
Mark D
MD
Behre
Gerhard
G
Hiddemann
Wolfgang
W
Ito
Yoshiaki
Y
Tenen
Daniel G
DG
D000208:Acute Disease; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006098:Granulocytes / Q000166:cytology; D006579:Heterozygote; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000473:pathology; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology; D000099232:Proto-Oncogene Protein Spi-1
D011518:Proto-Oncogene Proteins; D016186:Receptor, Macrophage Colony-Stimulating Factor; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1