Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia

San Raffaele Bio-medical Park Foundation, Rome, Italy.
Blood (Impact Factor: 10.45). 06/2007; 109(10):4432-40. DOI: 10.1182/blood-2006-09-045781
Source: PubMed


Alteration of lineage-specific transcriptional programs for hematopoiesis causes differentiation block and promotes leukemia development. Here, we show that AML1/ETO, the most common translocation fusion product in acute myeloid leukemia (AML), counteracts the activity of retinoic acid (RA), a transcriptional regulator of myelopoiesis. AML1/ETO participates in a protein complex with the RA receptor alpha (RARalpha) at RA regulatory regions on RARbeta2, which is a key RA target gene mediating RA activity/resistance in cells. At these sites, AML1/ETO recruits histone deacetylase, DNA methyltransferase, and DNA-methyl-CpG binding activities that promote a repressed chromatin conformation. The link among AML1/ETO, heterochromatic RARbeta2 repression, RA resistance, and myeloid differentiation block is indicated by the ability of either siRNA-AML1/ETO or the DNA methylation inhibitor 5-azacytidine to revert these epigenetic alterations and to restore RA differentiation response in AML1/ETO blasts. Finally, RARbeta2 is commonly silenced by hypermethylation in primary AML blasts but not in normal hematopoietic precursors, thus suggesting a role for the epigenetic repression of the RA signaling pathway in myeloid leukemogenesis.

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Available from: Lorena Travaglini
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    • "An alternative strategy has been to reverse DNA methylation through the use of the DNA methyltransferase inhibitor 5-azacytidine as a 'priming' agent for ATRA. Fazi et al. showed that in vitro alteration of methylation by 5-azacytidine restored retinoic acid-mediated differentiation in RUNX1-CBFA2T1 blasts [34]. In an attempt to target both DNA methylation and histone deacetylation, Soriano et al. developed a Phase II trial of the combination of 5-azacytidine with valproic acid and ATRA in 53 patients [47], and obtained an overall response rate of 42%. "
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    ABSTRACT: The success of all-trans retinoic acid (ATRA) therapy in acute promeylocytic leukemia (APL) has spawned numerous attempts to translate the paradigm of differentiation therapy to non-APL acute myelocytic leukemia (AML). However, the results of clinical trials have been overall disappointing. In this review we discuss the mechanism of retinoic acid signaling and the results of major clinical trials that have attempted to incorporate ATRA into AML regimens. We discuss recent evidence that indicate that the retinoic acid signaling pathway may be dysfunctional in AML. Preliminary studies suggest that targeting the pathways that modify retinoic acid receptor activity may reactivate the dormant retinoic acid-signaling pathway. Such strategies may revive the ability of ATRA to induce myeloid differentiation and apoptosis in non-APL AML. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Preview · Article · Jan 2015 · Blood Reviews
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    • "Both are found to form oligomeric complexes with the increased affinity for HDACs, and act as transcriptional repressors of differentiation-related genes. RA signaling pathway is silenced in AML1–ETO AMLs through recruitment of HDACs on regulatory sites, resulting in the transcriptional silencing of the RARβ2 gene which leads to RA resistance and differentiation block (66). AML1–ETO also interacts with essential hematopoietic transcription factors such as C/EBPα, PU.1, and GATA1 and blocks their differentiation-promoting functions (64). "
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    ABSTRACT: The concept of differentiation therapy of cancer is ~40 years old. Despite many encouraging results obtained in laboratories, both in vitro and in vivo studies, the only really successful clinical application of differentiation therapy was all-trans-retinoic acid (ATRA)-based therapy of acute promyelocytic leukemia (APL). ATRA, which induces granulocytic differentiation of APL leukemic blasts, has revolutionized the therapy of this disease by converting it from a fatal to a curable one. However, ATRA does not work for other acute myeloid leukemias (AMLs). Since 1,25-dihydroxyvitamin D3 (1,25D) is capable of inducing monocytic differentiation of leukemic cells, the idea of treating other AMLs with vitamin D analogs (VDAs) was widely accepted. Also, some types of solid cancers responded to in vitro applied VDAs, and hence it was postulated that VDAs can be used in many clinical applications. However, early clinical trials in which cancer patients were treated either with 1,25D or with VDAs, did not lead to conclusive results. In order to search for a molecular basis of such unpredictable responses of AML patients toward VDAs, we performed ex vivo experiments using patient's blast cells. Experiments were also performed using 1,25D-responsive and 1,25D-non-responsive cell lines, to study their mechanisms of resistance toward 1,25D-induced differentiation. We found that one of the possible reasons might be due to a very low expression level of vitamin D receptor (VDR) mRNA in resistant cells, which can be increased by exposing the cells to ATRA. Our considerations concerning the molecular mechanism behind the low VDR expression and its regulation by ATRA are reported in this paper.
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    • "RARβ is an RA-regulated tumor suppressor gene silenced by aberrant DNA methylation in acute promyelocytic leukemia (APL) and other human malignancies [23,24]. In human leukemia HL-60 and K562 cell lines RARβ gene is silenced [25]. "
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