PML RAR-ALPHA, A FUSION PROTEIN IN ACUTE PROMYELOCYTIC LEUKEMIA, PREVENTS GROWTH-FACTOR WITHDRAWAL-INDUCED APOPTOSIS IN TF-1 CELLS/

A unique mRNA produced by the t(15;17)(q22-24;q11-21) translocation in the leukemic cells of acute promyelocytic leukemia patients encodes a chimeric protein, PML/RAR alpha, which is formed by the fusion of the retinoic acid receptor alpha (RAR alpha) and the promyelocytic locus gene (PML), This translocation is often the only visible karyotypic ab erration present which is detected in almost 100% of acute promyelocyt ic leukemia patients, As an initial step to study the role of PML/RAR alpha in leukemogenesis, we attempted to express the fusion protein in hematopoietic cells through retrovirus-mediated gene transfer of the retroviral vector, pGPRCHT, which contains the PML/RAR alpha cDNA, Tra nsduction of the PML/RAR alpha cDNA fragment used in this vector, whic h extends from the position 31 bp to the position 2638 bp in a transcr iption unit driven by the Moloney murine sarcoma virus LTR, was found to abrogate the growth factor dependence of TF-1 cells, In addition, i ntroduction of PML/RAR alpha into TF-1 cells can protect these cells f rom the apoptosis usually induced in TF-1 cells by growth factor withd rawal, as measured by three assays for apoptosis: morphology, DNA ladd er formation, and end labeling of nicked DNA with fluorescent-conjugat ed nucleotide precursors followed by a fluorescence-activated cell sor ting assay, These data suggest that the PML/RAR alpha fusion protein m ay inhibit programmed cell death in myeloid cells.