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-RARalpha. This chimeric protein has been strongly implicated in APL pathogenesis because of its interactions with growth suppressors (PML), retinoid signaling molecules (RXRalpha), 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 RARalpha 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 RARalpha partner on chromosome 5, and both NPM-RARalpha and RARalpha-NPM fusion mRNAs were expressed in this patient. We further explored the effects of the NPM-RARalpha chimeric protein on the subcellular localization of PML, RXRalpha, 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, RXRalpha, and NPM-RARalpha in these cells. Our data support the hypothesis that while deregulation of both the retinoid signaling pathway and RARalpha partner proteins are molecular consequences of APL translocations, APL pathogenesis is not dependent on disruption of PML nuclear bodies.
Hummel
J L
JL
University of Toronto and the Institute of Medical Sciences, Ontario, Canada.
Wells
R A
RA
Dubé
I D
ID
Licht
J D
JD
Kamel-Reid
S
S
D002466:Cell Nucleolus; D002648:Child; D002886:Chromosomes, Human, Pair 17; D002895:Chromosomes, Human, Pair 5; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D008297:Male; D010750:Phosphoproteins / Q000235:genetics*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*; D014178:Translocation, Genetic; D020298:U937 Cells; D015854:Up-Regulation