Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.
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PMID:Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia. 2557 17

Epigenetic disorders play a key role in tumorigenesis and development, among which histone methylation abnormalities are common. While patients living with chronic myeloid leukemia in the chronic phase (CML-CP) have a good response to TKI, blastic phase (CML-BP) patients demonstrate poor efficacy and high fatality rates. However, while the mechanism of blast crisis of chronic myeloid leukemia remains unclear, high expression and activation of BCR-ABL are usually related to CML blast crisis transition. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL. In clinical specimens, the mRNA expression of RBP2 was found to be positively correlated with that of PTEN. These data suggest that the under-expression of RBP2 promotes blast crisis transition by activating an RBP2/PTEN/BCR-ABL cascade.
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PMID:Histone demethylase RBP2 mediates the blast crisis of chronic myeloid leukemia through an RBP2/PTEN/BCR-ABL cascade. 3137 92