Lentiviral PU.1 overexpression restores differentiation in myeloid leukemic blasts.
PU.1, a transcription factor of the ETS family, plays a pivotal role in normal hematopoiesis, and particularly in myeloid differentiation. Altered PU.1 function is possibly implicated in leukemogenesis, as PU.1 gene mutations were identified in some patients with acute myeloid leukemia (AML) and as several oncogenic products (AML1-ETO, promyelocytic leukemia-retinoic acid receptor alpha, FMS-like receptor tyrosine kinase 3 internal tandem duplication) are associated with PU.1 downregulation. To demonstrate directly a role of PU.1 in the blocked differentiation of leukemic blasts, we transduced cells from myeloid cell lines and primary blasts from AML patients with a lentivector encoding PU.1. In NB4 cells we obtained increases in PU.1 mRNA and protein, comparable to increases obtained with all-trans retinoic acid-stimulation. Transduced cells showed increased myelomonocytic surface antigen expression, decreased proliferation rates and increased apoptosis. Similar results were obtained in primary AML blasts from 12 patients. These phenotypic changes are characteristic of restored blast differentiation. PU.1 should therefore constitute an interesting target for therapeutic intervention in AML.
Durual
S
S
1Division of Hematology, University Hospital Geneva, Geneva, Switzerland.
Rideau
A
A
Ruault-Jungblut
S
S
Cossali
D
D
Beris
P
P
Piguet
V
V
Matthes
T
T
D000328:Adult; D000368:Aged; D017209:Apoptosis; D001752:Blast Crisis / Q000473:pathology*; D018826:CD13 Antigens / Q000235:genetics; D002454:Cell Differentiation; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D000099232:Proto-Oncogene Protein Spi-1
D018826:CD13 Antigens; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014212:Tretinoin; D000099232:Proto-Oncogene Protein Spi-1