Cytosine arabinoside (Ara-C) has been the standard therapeutic agent for myelodysplastic syndromes (MDS) and adult acute myeloid leukemia (AML) patients for decades. Considerable progress has been made in development of new treatments for MDS/AML patients, but drug resistance remains a major clinical problem. Apoptotic bodies (ABs), produced by late apoptotic cells, can enclose bioactive components that affect cell-cell interactions and disease progression. We isolated and identified drug-induced ABs from Ara-C-tolerance cells. Treatment of sensitive cells with Ara-C-induced ABs resulted in Ara-C-resistant phenotype. We further investigated components and functions of Ara-C-induced ABs. Proteomics analysis in combination with mass spectrometry revealed that Ara-C-induced ABs carried numerous RNA-binding proteins, notably including insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). Delivery of AB-encapsulated IGF2BP3 promoted survival of recipient cells by activating PI3K-AKT and p42-44 MAPK pathways. High IGF2BP3 level in ABs from MDS/AML patient plasma was correlated with poor overall survival. Our findings demonstrate that AB-derived IGF2BP3 plays an essential role in acquired Ara-C resistance in MDS/AML patients, and is a potential therapeutic target for suppression of Ara-C resistance.
Elevated TWIST1 expression in myelodysplastic syndromes/ acute myeloid leukemia reduces efficacy of hypomethylating therapy with decitabineMyelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral blood cytopenia, hematopoietic cell dysplasia, and transformation to secondary acute myeloid leukemia (AML) in 30% of cases. 1 Epigenetic changes are recognized as major drivers of MDS progression.A recent study indicates that DNA hypermethylation is a relevant parameter of MDS at the molecular level. 2Treatment with demethylating compounds, decitabine, such as 5azacytidine or 5-aza-2'-deoxycytidine (DAC) increased overall survival and delayed AML transformation. 3However, hypomethylating agents are ineffective in a substantial proportion of patients, for reasons which remain unclear.We showed previously that the highly conserved transcription factor TWIST1, which contains a basic helixloop-helix structure, is aberrantly upregulated in advanced MDS. 4 TWIST1 expression is regulated in turn by microRNA-10a/10b, and inhibition of miR-10a/10b in clonal cells interfered with its proliferation and enhanced its susceptibility to apoptosis. 5TWIST1 is associated with DNA methylation and chromosome modification in a variety of solid tumors. 6,7The goal of the present study is to clarify the role of TWIST1 in modification of epigenetic changes and alteration of DAC sensitivity in MDS/AML.We carried out a direct comparison of TWIST1 levels in cells from healthy individuals (HD) and MDS/AML patients who are unresponsive to DAC treatment (DAC-NR group) or are responsive to DAC treatment (DAC-R group).There was a significantly lower expression in healthy individuals than in patients with MDS/AML, consistent with our previous results.Levels of TWIST1 in DAC-R group approached those in healthy controls (Online Supplementary Figure S1A).More interestingly, we found that TWIST1 levels were higher in the DAC-NR group than in the DAC-R group (Figure 1A and Online Supplementary.Table S1).A receiver operating characteristic (ROC) curve was created to show the threshold value for optimal sensitivity (70%) and specificity (86.4%) of TWIST1 expression in the DAC-NR group versus the DAC-R group (Online Supplementary Figure S1B).Followup experiments showed that global methylation levels
Members of the ten‑eleven translocation (TET) protein family of which three mammalian TET proteins have been discovered so far, catalyze the sequential oxidation of 5‑methylcytosine to 5‑hydroxymethylcytosine, 5‑formylcytosine, and 5‑carboxylcytosine which serve an important role in embryonic development and tumor progression. O‑GlcNAcylation (O‑linked β‑N‑acetylglucosaminylation) is a reversible post‑translational modification known to serve important roles in tumorigenesis and metastasis especially in hematopoietic malignancies such as myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myeloid leukemia. O‑GlcNAcylation activity requires only two enzymes: O‑GlcNAc transferase (OGT) and O‑GlcNAcase (OGA). OGT catalyzes attachment of GlcNAc sugar to serine, threonine and cytosine residues in proteins, while OGA hydrolyzes O‑GlcNAc attached to proteins. Numerous recent studies have demonstrated that TETs can be O‑GlcNAcylated by OGT, with consequent alteration of TET activity and stability. The present review focuses on the cellular, biological and biochemical functions of TET and its O‑GlcNAcylated form and proposes a model of the role of TET/OGT complex in regulation of target proteins during cancer development. In addition, the present review provides directions for future research in this area.
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