PRAM-1 is a novel adaptor protein regulated by retinoic acid (RA) and promyelocytic leukemia (PML)-RA receptor alpha in acute promyelocytic leukemia cells

The t(15;17) translocation, found in 95% of acute promyelocytic leukemia, e ncodes a promyelocytic leukemia (PML)-retinoic acid receptor alpha (RAR alp ha) fusion protein. Complete remission of acute promyelocytic leukemia can be obtained by treating patients with all-trans retinoic acid, and PML-RAR alpha plays a major role in mediating retinoic acid effects in leukemia cel ls. A main model proposed for acute promyelocytic leukemia is that PML-RAR alpha exerts its oncogenic effects by repressing the expression of retinoic acid-inducible genes critical to myeloid differentiation. By applying subt raction cloning to acute promyelocytic leukemia cells, we identified a reti noic acid-induced gene, PRAM-1 ((P) under bar ML-RAR alpha target gene enco ding an (A) under bar daptor (M) under bar olecule-1), which encodes a nove l adaptor protein sharing structural homologies with the SLAP-130/fyb adapt or. PRAM-1 is expressed and regulated during normal human myelopoiesis. In U937 myeloid precursor cells, PRAM-1 expression is inhibited by expression of PML-RAR alpha in the absence of ligand and de novo superinduced by retin oic acid. PRAM-1 associates with other adaptors, SLP-76 and SKAP-55HOM, in myeloid cell lines and with protein tyrosine kinase lyn. By providing the f irst evidence that PML-RAR alpha dysregulates expression of an adaptor prot ein, our data open new insights into signaling events that are disrupted du ring transformation by PML-RAR alpha and induced by retinoic acid during de novo differentiation of acute promyelocytic leukemia cells.