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The Retinoic Acid Receptor (RAR) Chimeric Proteins PML-, PLZF-, NPM-, and NuMA-RAR Have Distinct Intracellular Localization Patterns¹

The Institute of Medical Sciences [J. L. H., R. A. W., S. K-R.] and Department of Laboratory Medicine and Pathobiology [S. K-R.], University of Toronto, Toronto, Ontario, M5S 1A8; The Ontario Cancer Institute, The Department of Pathology, The University Health Network, Toronto, Ontario, M5G 2M9 [J. L. H., T. Z., S. K-R.], Canada

Retinoic acid receptor (RAR) gene rearrangement by reciprocal chromosome translocation is the molecular signature of acutepromyelocytic leukemia (APL). Disruption of RAR function appears to be the likely cause of aberrant myelopoiesis observed in APL, because PML-RAR expression has been shown to deregulate the transcription of genes that control myelopoiesis. To target RAR chimeric proteins, we engineered epitope-tagged versions of PML-RAR, PLZF-RAR, NPM-RAR, and NuMA-RAR (X-RAR^V5) and generated a panel of stable COS cell lines expressing X-RAR^V5. Protein fractionation and Western analysis of these COS lines reveal that X-RAR proteins localize to both the cytoplasm and nucleus. NPM-RAR is predominantly nuclear whereas NuMA-RAR is predominantly cytoplasmic. Confocal immunofluorescent microscopy reveals that PML-RAR and PLZF-RAR share a primarily diffuse nuclear pattern that excludes the nucleolus. NPM-RAR is also diffuse in the nucleus but, in contrast to PML-RAR and PLZF-RAR, is strongly associated with the nucleolus. Strikingly, NuMA-RAR predominantly localizes throughout the cytoplasm in a microspeckled pattern. We further demonstrate that NPM and NuMA interact with NPM-RAR and NuMA-RAR, respectively. The distinct intracellular localization patterns and the shared ability of X-RAR to interact with their respective RAR partner proteins (X) further support the hypothesis that deregulation of these partners may play a role in APL pathogenesis.

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