Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RAR alpha and NPM-RAR alpha

Acute promyelocytic leukemia (APL) is characterized by a specific chromosom e translocation involving RAR alpha and one of four fusion partners: PML, P LZF, INPM, and NuMA genes. To study the leukemogenic potential of the fusio n genes in vivo, We generated transgenic mice with PLZF-RAR alpha and NPM-R AR alpha. PLZF-RAR alpha transgenic animals developed chronic myeloid leuke mia-like phenotypes at an early stage of life within 3 months in five of si x mice), whereas three NPM-RAR alpha transgenic mice showed a spectrum of p henotypes from typical APL to chronic myeloid leukemia relatively late in l ife (from 12 to 15 months). In contrast to bone marrow cells from PLZF-RAR alpha transgenic mice, those from NPM-RAR alpha transgenic mice could be in duced to differentiate by all-trans-retinoic acid (ATRA). We also studied R ARE binding properties and interactions between nuclear corepressor SMRT an d various fusion proteins in response to ATRA. Dissociation of SMRT from di fferent receptors was observed at ATRA concentrations of 0.01 mu M, 0.1 mu M, and 1.0 mu M for RAR alpha-RXR alpha, NPM-RAR alpha, and PML-RAR alpha, respectively, but not observed for PLZF-RAR alpha( even in the presence of 10 mu M ATRA We also determined the expression of the tissue factor gene in transgenic mice, which was detected only in bone marrow cells of mice expr essing the fusion genes. These data clearly establish the leukemogenic role of PLZF-RAR alpha and NPM-RAR alpha and the importance of fusion receptor/ corepressor interactions in the pathogenesis as well as in determining diff erent clinical phenotypes of APL.