Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acute promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARalpha) fusion product recruits histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities on retinoic acid (RA)-target promoters causing their silencing and differentiation block. RA treatment induces epigenetic modifications at its target loci and restores myeloid differentiation of APL blasts. Using RA-sensitive and RA-resistant APL cell lines and primary blasts, we addressed the functional relevance of the aberrant methylation status at the RA-target promoter RARbeta2 and the mechanism by which methylation is reversed by RA. RA decreased DNMT expression and activity, which correlated with demethylation at specific sites on RARbeta2 promoter/exon-1, and the ability of APL blasts to differentiate in vitro and in vivo. None of these events occurred in an RA-resistant APL cell line containing a PML-RARalpha defective for ligand binding. The specific contribution of the HDAC and DNMT pathways to the response of APL cells to RA was also tested by inhibiting these enzymatic activities with TSA and/or 5-azacytidine. In RA-responsive and RA-resistant APL blasts, TSA and 5-azacytidine induced specific changes on the chromatin state at RA-target sites, increased the RA effect on promoter activity, endogenous RA-target gene expression and differentiation. These results extend the rationale for chromatin-targeted treatment in APL and RA-resistant leukemias.
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PMID:Retinoic acid targets DNA-methyltransferases and histone deacetylases during APL blast differentiation in vitro and in vivo. 1568 37

Although molecular targeted therapies have recently displayed therapeutic effects in acute myeloid leukemia (AML), limited response and acquired resistance remain common problems. Numerous studies have associated autophagy, an essential degradation process involved in the cellular response to stress, with the development and therapeutic response of cancers including AML. Thus, we review studies on the role of autophagy in AML development and summarize the linkage between autophagy and several recurrent genetic abnormalities in AML, highlighting the potential of capitalizing on autophagy modulation in targeted therapy for AML. Abbreviations: AML: acute myeloid leukemia; AMPK: AMP-activated protein kinase; APL: acute promyelocytic leukemia; ATG: autophagy related; ATM: ATM serine/threonine kinase; ATO: arsenic trioxide; ATRA: all trans retinoic acid; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BET proteins, bromodomain and extra-terminal domain family; CMA: chaperone-mediated autophagy; CQ: chloroquine; DNMT, DNA methyltransferase; DOT1L: DOT1 like histone lysine methyltransferase; FLT3: fms related receptor tyrosine kinase 3; FIS1: fission, mitochondrial 1; HCQ: hydroxychloroquine; HSC: hematopoietic stem cell; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; KMT2A/MLL: lysine methyltransferase 2A; LSC: leukemia stem cell; MDS: myelodysplastic syndromes; MTORC1: mechanistic target of rapamycin kinase complex 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NPM1: nucleophosmin 1; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PML: PML nuclear body scaffold; ROS: reactive oxygen species; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAHA: vorinostat; SQSTM1: sequestosome 1; TET2: tet methylcytosine dioxygenase 2; TKD: tyrosine kinase domain; TKI: tyrosine kinase inhibitor; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VPA: valproic acid; WDFY3/ALFY: WD repeat and FYVE domain containing 3.
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PMID:The role of autophagy in targeted therapy for acute myeloid leukemia. 3291 24