Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) locus on chromosome 17. In the majority of cases, RARalpha translocates and fuses with the promyelocytic leukemia (PML) gene located on chromosome 15. The resulting fusion genes encode the two structurally unique PML/RARalpha and RARalpha/PML fusion proteins as well as aberrant PML gene products, the respective pathogenetic roles of which have not been elucidated. We have generated transgenic mice in which the PML/RARalpha fusion protein is specifically expressed in the myeloid-promyelocytic lineage. During their first year of life, all the PML/RARalpha transgenic mice have an abnormal hematopoiesis that can best be described as a myeloproliferative disorder. Between 12 and 14 months of age, 10% of them develop a form of acute leukemia with a differentiation block at the promyelocytic stage that closely mimics human APL even in its response to retinoic acid. Our results are conclusive in vivo evidence that PML/RARalpha plays a crucial role in the pathogenesis of APL.
|Titolo:||Acute leukemia with promyelocytic features in PML/RARalpha transgenic mice|
|Parole Chiave:||Chromosomes, Human, Pair 17; Animals; Hematopoietic Stem Cells; Humans; Aging; Lymphocytes; Mice, Transgenic; Bone Marrow; Receptors, Retinoic Acid; Nuclear Proteins; Transcription Factors; DNA Primers; Leukemia, Promyelocytic, Acute; Reference Values; Myeloproliferative Disorders; Cell Differentiation; Spleen; Mice; Recombinant Fusion Proteins; Hematopoiesis; Blood Cell Count; Translocation, Genetic; Tumor Suppressor Proteins; Polymerase Chain Reaction; Neoplasm Proteins; Tretinoin|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||13-mag-1997|
|Digital Object Identifier (DOI):||10.1073/pnas.94.10.5302|
|Appare nelle tipologie:||01 - Articolo su periodico|