Translocations of the RARα gene in acute promyelocytic leukemia

Zelent, Arthur; Guidez, Fabien; Melnick, Ari; Waxman, Samuel; Licht, Jonathan D.

doi:10.1038/sj.onc.1204766

Cited by 204 publications

(187 citation statements)

References 201 publications

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“…APL is commonly due to translocations affecting the RARa locus (reviewed by Zelent et al, 2001). The most common genetic cause of APL is t(15;17), which rearranges the PML and RAR genes.…”

Section: Hdac3 In Leukemiamentioning

confidence: 99%

HDAC3: taking the SMRT-N-CoRrect road to repression

2007

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Known histone deacetylases (HDACs) are divided into different classes, and HDAC3 belongs to Class I. Through forming multiprotein complexes with the corepressors SMRT and N-CoR, HDAC3 regulates the transcription of a plethora of genes. A growing list of nonhistone substrates extends the role of HDAC3 beyond transcriptional repression. Here, we review data on the composition, regulation and mechanism of action of the SMRT/ N-CoR-HDAC3 complexes and provide several examples of nontranscriptional functions, to illustrate the wide variety of physiological processes affected by this deacetylase. Furthermore, we discuss the implication of HDAC3 in cancer, focusing on leukemia. We conclude with some thoughts about the potential therapeutic efficacies of HDAC3 activity modulation.

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“…APL is commonly due to translocations affecting the RARa locus (reviewed by Zelent et al, 2001). The most common genetic cause of APL is t(15;17), which rearranges the PML and RAR genes.…”

Section: Hdac3 In Leukemiamentioning

confidence: 99%

HDAC3: taking the SMRT-N-CoRrect road to repression

2007

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“…Patients with chromosomal breakpoints in bcr1, bcr2 or bcr3 express either the long (L), the medium (M) or the short (S) isoform of the PML-RARa protein (Pandolfi et al, 1992). The RNA encoding the PML-RARa L isoform can be alternatively spliced to give PML-RARa M (medium) isoform, which is usually coexpressed with the long isoform in a given patient (Zelent et al, 2001). Although the transcriptional functions of the PML-RARaS have been well studied, much less is known about the mechanism of action of the long isoform.…”

Section: Resultsmentioning

confidence: 99%

“…Among newly diagnosed patients, those who expressed the short isoform appeared to have shorter disease-free and overall survival durations than patients who expressed the long isoform (Jurcic et al, 2001;Sucic et al, 2002). PML-RARa L isoform is expressed in approximately 55% of adult patients with APL, while the S and V isoforms are expressed in approximately 35 and 8% of patients, respectively (Zelent et al, 2001). In the pediatric population, the V isoform accounts for a larger proportion of cases than in adults (Kane et al, 1996), with a corresponding decrease in the number of PML-RARa S cases.…”

Section: Introductionmentioning

confidence: 99%

Pro-proliferative function of the long isoform of PML-RARα involved in acute promyelocytic leukemia

2006

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“…(45) APL is usually accompanied by t(15;17), which forms the PML-RARA fusion gene. (46) In addition, molecular variants of APL have been described in which RARA is fused to one of four other genes: PLZF, NUMA, STAT5b or NPM1. (46,47) Common features of all of these proteins are that the B through F regions of RARα, which contain its DNA and ligand-binding domains, have N-terminal non-RARα moieties that add dimerization ability to each fusion protein.…”

Section: Npm-rarα α α α Chimeric Transcription Factor In Aplmentioning

confidence: 99%

Nucleophosmin: A versatile molecule associated with hematological malignancies

Naoe

Suzuki

Kiyoi³

et al. 2006

Cancer Science

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Nucleophosmin (NPM) is a nucleolar phosphoprotein that plays multiple roles in ribosome assembly and transport, cytoplasmicnuclear trafficking, centrosome duplication and regulation of p53. In hematological malignancies, the NPM1 gene is frequently involved in chromosomal translocation, mutation and deletion. The NPM1 gene on 5q35 is translocated with the anaplastic lymphoma kinase (ALK) gene in anaplastic large cell lymphoma with t(2;5). The MLF1 and RARA genes are fused with NPM1 in myelodysplastic syndrome and acute myeloid leukemia (AML) with t(3;5) and acute promyelocytic leukemia with t(5;17), respectively. In each fused protein, the Nterminal NPM portion is associated with oligomerization of a partner protein leading to altered signal transduction or transcription. Recently, mutations of exon 12 have been found in a significant proportion of de novo AML, especially in those with a normal karyotype. Mutant NPM is localized aberrantly in the cytoplasm, but the molecular mechanisms for leukemia remain to be studied. N ucleophosmin (NPM), also called B23, numatrin or NO38, was isolated as an abundant nucleolar phosphoprotein, whose expression level is increased significantly by several kinds of stimulation and transformation. (1,2) In 1989, a human NPM cDNA encoding a 294-amino-acid protein was cloned. (3) In 2002, a shorter isoform encoding a 259-amino acid protein that differs at the C-terminus was also isolated. (4) The NPM1 gene spans 25 kb, contains 12 exons and maps to chromosome 5q35. (4,5) Exon 8 is frequently skipped, and exon 10 is used only for the short isoform. Although the biological significance of the short isoform remains unclear, its expression is increased in radiation-insensitive cell lines and the product is localized in the cytoplasm as well as in the nucleus. (4,6) The structural features of NPM consist of an oligomerization domain, a metalbinding motif, a bipartite nuclear localization signal, two Asp/ Glu-rich domains, phosphorylation sites for CDK2 and a nucleor localization signal. (6,7) NPM1 has been recognized by oncologists as a partner gene for various chromosomal translocations: NPM-anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) with t(3;5), NPM-RARA in acute promyelocytic leukemia (APL) with t(5;17), and NPM-MLF1 in acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS) with t(3;5). (8)(9)(10) (Fig. 1, 2) In each chimeric gene product, the N-terminal NPM portion is thought to act as the interface for oligomerization and oncogenic conversion of the C-terminal functional domain such as a kinase or transcription factor. Recently, NPM was associated with centrosome duplication and the regulation of p53, (11,12) and might have a role as a tumor suppressor. Expression and function of NPMNucleophosmin is an abundant and ubiquitously expressed phosphoprotein. It is located mainly in the nucleolus and shuttles between the nucleus and cytoplasm. (13,14) NPM has been proposed to be associated with the synthesis and processing of ribosomal RNA (rRNA), regu...

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Translocations of the RARα gene in acute promyelocytic leukemia

Cited by 204 publications

References 201 publications

HDAC3: taking the SMRT-N-CoRrect road to repression

HDAC3: taking the SMRT-N-CoRrect road to repression

Pro-proliferative function of the long isoform of PML-RARα involved in acute promyelocytic leukemia

Nucleophosmin: A versatile molecule associated with hematological malignancies

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