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

Abstract

Greater than 95% of acute promyelocytic leukemia (APL) cases are associated with the expression of PML-RARα. This chimeric protein has been strongly implicated in APL pathogenesis because of its interactions with growth suppressors (PML), retinoid signaling molecules (RXRα), and nuclear hormone transcriptional co-repressors (N-CoR and SMRT). A small number of variant APL translocations have also been shown to involve rearrangements that fuse RARα 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 RARα partner on chromosome 5, and both NPM-RARα and RARα-NPM fusion mRNAs were expressed in this patient. We further explored the effects of the NPM-RARα chimeric protein on the subcellular localization of PML, RXRα, NPM, and PLZF using immunofluorescent confocal microscopy. While PML remained localized to its normal 10 – 20 nuclear bodies, NPM nucleolar localization was disrupted and PLZF expression was upregulated in a microspeckled pattern in patient leukemic bone marrow cells. We also observed nuclear co-localization of NPM, RXRα, and NPM-RARα in these cells. Our data support the hypothesis that while deregulation of both the retinoid signaling pathway and RARα partner proteins are molecular consequences of APL translocations, APL pathogenesis is not dependent on disruption of PML nuclear bodies.

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Acknowledgements

We are indebted to M Freedman, W Vanek and T Grunberger (Hospital for Sick Children, Toronto, Canada) for providing patient material for our studies and for help with the interpretation of clinical information; C Jones and D Geyer of the Eleanor Roosevelt Institute in Denver, Colorado for their expertise in creating the panel of somatic cell hybrids: and to M Starr for assistance with confocal microscopy (Hospital for Sick Children, Toronto, Canada). This work was partially funded by the Leukemia Research Fund (S Kamel-Reid), the National Cancer Institute of Canada (S Kamel-Reid), and NIH R01 CA 59936 (JD Licht). JD Licht is a Scholar of the Leukemia Society of America.

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Hummel, J., Wells, R., Dubé, I. et al. Deregulation of NPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia. Oncogene 18, 633–641 (1999). https://doi.org/10.1038/sj.onc.1202357

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