Retinoid target genes in acute promyelocytic leukemia

Pitha-Rowe, Ian; Petty, W. Jeffrey; Kitareewan, Sutisak; Dmitrovsky, Ethan

doi:10.1038/sj.leu.2403065

Cited by 69 publications

(71 citation statements)

References 88 publications

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“…2A). Although modulations of C͞EBPs, including C͞EBP␣, -␤, and -in the RA-induced granulocyte differentiation have been reported (9,10), there was a lack of coherent data in terms of the complex roles played by C͞EBPs. It has been shown that dimerization of different C͞EBP proteins precisely regulates the transcriptional activity of target genes (11).…”

Section: Resultsmentioning

confidence: 99%

Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia

Zheng

Wang

Zhang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

239

188

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Understanding the complexity and dynamics of cancer cells in response to effective therapy requires hypothesis-driven, quantitative, and high-throughput measurement of genes and proteins at both spatial and temporal levels. This study was designed to gain insights into molecular networks underlying the clinical synergy between retinoic acid (RA) and arsenic trioxide (ATO) in acute promyelocytic leukemia (APL), which results in a high-quality disease-free survival in most patients after consolidation with conventional chemotherapy. We have applied an approach integrating cDNA microarray, 2D gel electrophoresis with MS, and methods of computational biology to study the effects on APL cell line NB4 treated with RA, ATO, and the combination of the two agents and collected in a time series. Numerous features were revealed that indicated the coordinated regulation of molecular networks from various aspects of granulocytic differentiation and apoptosis at the transcriptome and proteome levels. These features include an array of transcription factors and cofactors, activation of calcium signaling, stimulation of the IFN pathway, activation of the proteasome system, degradation of the PML-RAR␣ oncoprotein, restoration of the nuclear body, cell-cycle arrest, and gain of apoptotic potential. Hence, this investigation has provided not only a detailed understanding of the combined therapeutic effects of RA͞ATO in APL but also a road map to approach hematopoietic malignancies at the systems level.systems biology ͉ self-organizing map A cute promyelocytic leukemia (APL) is a form of acute myeloid leukemia that responds remarkably to the effect of differentiation-induction by all-trans-retinoic acid and the differentiation͞ apoptosis-inducing effect of arsenic trioxide (ATO). Cytogenetically, a translocation t(15;17)(q22;q21) is found in most APL patients, resulting in the formation of the promyelocytic leukemiaretinoic acid receptor ␣ (PML-RAR␣) fusion gene (1). The chimeric protein encoded by the fusion gene oligomerizes with retinoid-X receptor (RXR) and disrupts the retinoic acid (RA) signal pathway, which is essential for granulocytic differentiation. PML-RAR␣ can also form a homodimer that competes with RAR␣ for binding to the RA-response elements of target genes and binds to the corepressor (CoR) complex with a much higher affinity than does the wild-type RAR␣͞RXR. This change leads to transcriptional repression under physiological concentrations of RA and, thus, blocks cell differentiation. Pharmacological concentrations of RA can convert the PML-RAR␣ fusion protein from a transcription repressor to a transcription activator, resulting in the release of the CoR and the recruitment of a coactivator (CoA) complex. The RA treatment can also trigger degradation of the PML-RAR␣ protein via the ubiquitin͞proteasome (U͞P) pathway and, thus, trigger reassembly of the nuclear body (NB) (2). On the other hand, ATO induces partial differentiation and͞or apoptosis of APL cells in a dose-dependent manner. Importantly, cellular and m...

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Section: Resultsmentioning

confidence: 99%

Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia

Zheng

Wang

Zhang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

239

188

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“…The nature of the fusion partner has an important bearing on disease characteristics, determining the sensitivity to ATRA and arsenic trioxide (reviewed in Mistry et al 1 ). Work from a number of laboratories has revealed that at physiological levels of RA, XRARa proteins bind corepressor/histone deacetylase (HDAC) complexes at significantly higher affinity than wild-type RARa; which leads to repression of retinoid target genes which is likely to play a key role in mediating the differentiation block that characterizes APL (reviewed in Pitha-Rowe et al 7 ). The transcriptional repression of target genes has recently been shown to be further compounded by recruitment of DNA methyltransferases leading to methylation of key promoters.…”

Section: Introductionmentioning

confidence: 99%

“…8 In the presence of pharmacological levels of RA, ligand binding induces a conformational change in the PML-RARa fusion protein accompanied by the release of corepressor/HDAC complex in favor of coactivator binding leading to transcriptional activation of downstream targets. 7 In addition, RA leads to degradation of PML-RARa and release of sequestered RXR, which all together lead to differentiation of the leukemic clone culminating in apoptosis, associated with upregulation of TRAIL. 9,10 This scenario contrasts with the rarer subtype of APL with the PLZF-RARa fusion in which corepressor/HDAC complexes additionally bind to the amino-terminal PLZF moiety in a retinoid-insensitive fashion, such that this subgroup of APL responds poorly to ATRA as single agent therapy.…”

Section: Introductionmentioning

confidence: 99%

Acute promyelocytic leukemia: where does it stem from?

Grimwade

Enver

2004

Leukemia

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A fundamental issue in cancer biology is the identification of the target cell in which the causative molecular lesion arises. Acute myeloid leukemia (AML) is thought to reflect the transformation of a primitive stem cell compartment. The resultant 'cancer stem cells' comprise only a minor portion of the leukemic clone but give rise through differentiation to more committed progenitors as well as differentiated blasts that constitute the bulk of the tumor. The maintenance of the leukemic clone is dependent on the self-renewal capacity of the cancer stem cell compartment, which is revealed by its ability to re-initiate leukemia in a transplant setting. The cellular basis of acute promyelocytic leukemia (APL) is however less clear. APL has traditionally been considered to be the most differentiated form of AML and to arise from a committed myeloid progenitor. Here we review apparently conflicting evidence pertaining to the cellular origins of APL and propose that this leukemia may originate in more than one cellular compartment. This view could account for many apparent inconsistencies in the literature to date. An understanding of the nature of the target cell involved in transformation of APL has important implications for biological mechanism and for clinical treatment.

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“…In the absence of ligand, retinoid receptors bind specific retinoic-acid response elements on target genes and recruit nuclear co-repressors, such as NCOR (nuclear receptor co-repressor) and SMRT (silencing mediator of RAR and thyroid hormone receptor). Retinoid binding to these receptors leads to release of corepressors and recruitment of transcriptional co-activators to regulate a diverse range of genes involved in transcriptional and apoptosis regulation, proliferation and protein modification [17].…”

Section: Retinoic Acid Receptorsmentioning

confidence: 99%

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

Labeur

Paez-Pereda²,

Arzt

et al. 2008

Rev Endocr Metab Disord

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Cushing's disease is a severe clinical condition caused by hypersecretion of corticosteroids due to excessive ACTH secretion from a pituitary adenoma. This complex endocrine disorder still represents a major challenge for the physician in terms of efficient treatment. In the last years there was only little progress in elucidating the molecular mechanisms responsible for the constitutive and autonomous ACTH secretion of pituitary corticotrophinomas. As a consequence, no effective drug therapy is currently available, particularly if surgical excision is not successful. In the present article we examine recent studies that have investigated the therapeutic potential of retinoic acid receptors as nuclear receptor targets for the treatment of Cushing's disease. Retinoic acid is an efficient drug used for the treatment of different types of cancers and it proved to act in animal models of Cushing's disease. The efficiency of this treatment in patients with this disorder still needs to be tested in clinical trials.

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Retinoid target genes in acute promyelocytic leukemia

Cited by 69 publications

References 88 publications

Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia

Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia

Acute promyelocytic leukemia: where does it stem from?

Potential of retinoic acid derivatives for the treatment of corticotroph pituitary adenomas

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