THE ACUTE PROMYELOCYTIC LEUKEMIA-SPECIFIC PML-RAR-ALPHA FUSION PROTEIN INHIBITS DIFFERENTIATION AND PROMOTES SURVIVAL OF MYELOID PRECURSOR CELLS

Acute promyelocytic leukemia is a clonal expansion of hematopoietic pr ecursors blocked at the promyelocytic stage. The differentiation block can be reversed by retinoic acid, which induces blast maturation both in vitro and in vivo. Acute promyelocytic leukemia is characterized b y a 15;17 chromosome translocation with breakpoints within the retinoi c acid alpha receptor (RARalpha) gene on 17 and the PML gene, which en codes a putative transcription factor, on 15. A PML-RARalpha fusion pr otein is formed as a consequence of the translocation. We expressed th e PML-RARalpha protein in U937 myeloid precursor cells and showed that they lost the capacity to differentiate under the action of different stimuli (vitamin D3 and transforming growth factor beta1), acquired e nhanced sensitivity to retinoic acid, and exhibited a higher growth ra te consequent to diminished apoptotic cell death. These results provid e evidence of biological activity of PML-RARalpha and recapitulate cri tical features of the promyelocytic leukemia phenotype.