Retinoic acid targets DNA-methyltransferases and histone deacetylases during APL blast differentiation in vitro and in vivo

Fazi, Francesco; Travaglini, Lorena; Carotti, Daniela; Palitti, Franco; Diverio, Daniela; Alcalay, Myriam; McNamara, Suzan; Miller, Wilson H.; Coco, Francesco Lo; Pelicci, Pier Giuseppe; Nervi, Clara

doi:10.1038/sj.onc.1208286

Cited by 84 publications

(78 citation statements)

References 57 publications

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“…A decrease in DNA methyltransferase expression upon RA treatment may be of relevance to restore normal gene transcription (Fazi F et al, 2005), a finding that is in agreement with the reported efficacy of methyltransferase inhibitors in the treatment of hematological malignancies (Leone et al, 2003).…”

Section: Discussionsupporting

confidence: 77%

Molecular signature of retinoic acid treatment in acute promyelocytic leukemia

et al. 2005

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Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by a block of differentiation at the promyelocytic stage. APL patients respond to pharmacological concentrations of all-trans retinoic acid ( RA) and disease remission correlates with terminal differentiation of leukemic blasts. The PML/RAR oncogenic transcription factor is responsible for both the pathogenesis of APL and for its sensitivity to RA. In order to identify physiological targets of RA therapy, we analysed gene expression profiles of RA-treated APL blasts and found 1056 common target genes. Comparing these results to those obtained in RA-treated U937 cell lines revealed that transcriptional response to RA is largely dependent on the expression of PML/RAR. Several genes involved in the control of differentiation and stem cell renewal are early targets of RA regulation, and may be important effectors of RA response. Modulation of chromatin modifying genes was also observed, suggesting that specific structural changes in local chromatin domains may be required to promote RA-mediated differentiation. Computational analysis of upstream genomic regions in RA target genes revealed nonrandom distribution of transcription factor binding sites, indicating that specific transcriptional regulatory complexes may be involved in determining RA response

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Section: Discussionsupporting

confidence: 77%

Molecular signature of retinoic acid treatment in acute promyelocytic leukemia

et al. 2005

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“…[31][32][33] Both PML and DNMT3A regulate telomere function, and all-trans retinoic acid, which is part of the therapy for patients with t(15;17), down-regulates DNMT3A expression. 34,35 Together, these data suggest that DNMT3A mutations and the favorable-risk fusion oncogenes (e.g., PML-RARA and AML-ETO) may not be found in the same AML genomes because they both act to alter the function of DNA methyltransferases and are therefore redundant. However, the outcomes for patients with DNMT3A mutations and those with a favorable-risk cytogenetic profile are dramatically different, for reasons that are currently unclear.…”

Section: Discussionmentioning

confidence: 96%

DNMT3A mutations in acute myeloid leukemia

Shah

Licht

2011

Nat Genet

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“…However, it is still debated whether de novo epigenetic changes at both histone and DNA level are random, or rather the consequence of upstream mutational events (Baylin and Bestor, 2002). There is evidence that PML-RARA, the fusion protein associated with the t(15;17) translocation of acute promyelocytic leukemia, can induce aberrant hypermethylation of a retinoic acid receptor alpha (RAR alpha)-target gene in hematopoietic cells (Di Croce et al, 2002;Fazi et al, 2005). Here we show that expression of AML1-MTG16, the fusion protein associated with the t(16;21)-positive myelogenous leukemia, can induce myeloid maturation block in association with Csf1r epigenetic downregulation.…”

Section: Discussionmentioning

confidence: 99%

Myeloid maturation block by AML1-MTG16 is associated with Csf1r epigenetic downregulation

et al. 2005

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De novo epigenetic changes at histone and DNA level that affect gene transcription in cancer may be less random than we originally thought. Leukemia fusion proteins associated with specific chromosome translocations could mechanistically determine the epigenetic fate of specific target genes critical for normal hematopoiesis. This seems to be the case with AML1-MTG16, a fusion protein resulting from the t(16;21) translocation, a hallmark of therapy-related leukemia and myelodysplastic syndrome. Here we show that AML1-MTG16 blocks both myeloid differentiation and proliferation in the 32D/WT1-mouse myeloid cell line. These biological effects can be traced to the AML1 and MTG16 moieties of the fusion protein, respectively. Further, we show that AML1-MTG16 can induce epigenetic repressive changes at the histone and DNA level of the AML1 target gene Csf1r (c-fms), encoding the macrophage colony stimulating factor receptor. We observed that, concomitant with Csf1r downregulation, 32D/WT1 cells lost the ability to undergo myeloid differentiation in response to the granulocyte macrophage colony-stimulating factor (GM-CSF). Thus, there seems to be an association between AML1-MTG16-induced myeloid maturation block and epigenetic changes of a myeloid master gene.

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Retinoic acid targets DNA-methyltransferases and histone deacetylases during APL blast differentiation in vitro and in vivo

Cited by 84 publications

References 57 publications

Molecular signature of retinoic acid treatment in acute promyelocytic leukemia

Molecular signature of retinoic acid treatment in acute promyelocytic leukemia

DNMT3A mutations in acute myeloid leukemia

Myeloid maturation block by AML1-MTG16 is associated with Csf1r epigenetic downregulation

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