Deregulation of NPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia

Greater than 95% of acute promyelocytic leukemia (APL) cases are associated with the expression of PML-RAR alpha. This chimeric protein has been stron gly implicated in APL pathogenesis because of its interactions with growth suppressors (PML), retinoid signaling molecules (RXR alpha), and nuclear ho rmone transcriptional co-repressors (N-CoR and SMRT), A small number of var iant APL translocations have also been shown to involve rearrangements that fuse RAR alpha to partner genes other than PML, namely PLZF, NPM, and NuMA . We describe the molecular characterization of a t(5;17)(q35;q21) variant translocation involving the NPM gene, identified in a pediatric case of APL , RT-PCR, cloning, and sequence studies identified NPM as the RAR alpha par tner on chromosome 5, and both NPM-RAR alpha and RAR alpha-NPM fusion mRNAs were expressed in this patient. We further explored the effects of the NPM -RAR alpha chimeric protein on the subcellular localization of PML, RXR alp ha, NPM, and PLZF using immunofluorescent confocal microscopy. While PML re mained localized to its normal 10-20 nuclear bodies, NPM nucleolar localiza tion was disrupted and PLZF expression was upregulated in a microspeckled p attern in patient leukemic bone marrow cells, We also observed nuclear co-l ocalization of NPM, RXRa, and NPM-RAR alpha in these cells. Our data suppor t the hypothesis that while deregulation of both the retinoid signaling pat hway and RAR alpha partner proteins are molecular consequences of APL trans locations, APL pathogenesis is not dependent on disruption of PML nuclear b odies.