Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MicroRNAs are frequently deregulated in cancer. Here we show that miR-22 is upregulated in myelodysplastic syndrome (MDS) and leukemia and its aberrant expression correlates with poor survival. To explore its role in hematopoietic stem cell function and malignancy, we generated transgenic mice conditionally expressing miR-22 in the hematopoietic compartment. These mice displayed reduced levels of global 5-hydroxymethylcytosine (5-hmC) and increased hematopoietic stem cell self-renewal accompanied by defective differentiation. Conversely, miR-22 inhibition blocked proliferation in both mouse and human leukemic cells. Over time, miR-22 transgenic mice developed MDS and hematological malignancies. We also identify TET2 as a key target of miR-22 in this context. Ectopic expression of TET2 suppressed the miR-22-induced phenotypes. Downregulation of TET2 protein also correlated with poor clinical outcomes and miR-22 overexpression in MDS patients. Our results therefore identify miR-22 as a potent proto-oncogene and suggest that aberrations in the miR-22/TET2 regulatory network are common in hematopoietic malignancies.
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PMID:The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. 2382 2

TET2 protein is encoded by the gene TET2 which specifically catalyses the demethylation of 5-methylcytosine to cytosine. Mutations in TET2 have been identified in a number of haematological malignancies, including leukaemias and lymphomas. In acute myeloid leukaemia (AML), loss of TET2 function drives DNA methylation and gene silencing, contributing to disease pathogenesis and progression, making it an interesting target. Although such mutations are considered rare, there is an increasing body in the literature identifying them as unfavourable prognostic markers in AML. The hypomethylating agent nucleoside analogue 5-azacytidine is used in the treatment of AML and other haematological malignancies i.e. myelodysplastic syndrome (MDS). It functions by re-activating silenced genes is responsible for cytosine methylation, thereby driving differentiation and also promoting apoptosis of dysfunctional haematological cells. The present review article deals with the consequences of DNA methylation in relation to TET2 in AML, focusing on the potential prognostic effect of TET2 gene mutations, along with demethylating epigenetic strategies towards prediction of therapeutic response. The necessity for personalized therapeutic regimes, especially for older patients suffering from AML with mutated TET2 and/or other genetic alterations, along with its prognostication are also underlined.
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PMID:Acute myeloid leukaemia: recent data on prognostic gene mutations, in relation to stratified therapies for elderly patients. 3164 75