Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone lysine methylation and demethylation are considered critical steps in transcriptional regulation. In this report, we performed chromatin immunoprecipitation with microarray technology (ChIP-chip) analysis to examine the genome-wide occupancy of H3K9-me2 during all-trans-retinoic acid (ATRA)-induced differentiation of HL-60 promyelocytic leukemia cells. Using this approach, we found that KDM3B, which contains a JmjC domain, was downregulated during differentiation through the recruitment of a corepressor complex. Furthermore, KDM3B displayed histone H3K9-me1/2 demethylase activity and induced leukemogenic oncogene lmo2 expression via a synergistic interaction with CBP. Here, we found that KDM3B repressed leukemia cell differentiation and was upregulated in blood cells from acute lymphoblastic leukemia (ALL)-type leukemia patients. The combined results of this study provide evidence that the H3K9-me1/2 demethylase KDM3B might play a role in leukemogenesis via activation of lmo2 through interdependent actions with the histone acetyltransferase (HAT) complex containing CBP.
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PMID:KDM3B is the H3K9 demethylase involved in transcriptional activation of lmo2 in leukemia. 2261 88

KDM3B reportedly shows both tumor-suppressive and tumor-promoting activities in leukemia. The function of KDM3B is likely cell-type dependent and its seeming functional discordance may reflect its phenotypic dependence on downstream targets. Here, we first showed the underexpression of KDM3B in acute myeloid leukemia (AML) patients and AML cell lines with MLL-AF6/9 or PML-RARA translocations. Overexpression of KDM3B repressed colony formation of AML cell line with 5q deletion. We then performed global microarray profiling to identify potential downstream targets of KDM3B, notably HOXA1, which was verified by real time PCR and Western blotting. We further showed KDM3B binding at retinoic acid response elements (RARE) but not at the promoter region of HOXA1 gene. KDM3B knockdown resulted in increased mono-methylation but decreased di-methylation of H3K9 at RARE while eschewing the promoter region of HOXA1. Collectively, we found that KDM3B exhibits potential tumor-suppressive activity and transcriptionally modulates HOXA1 expression via RARE in AML.
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PMID:KDM3B shows tumor-suppressive activity and transcriptionally regulates HOXA1 through retinoic acid response elements in acute myeloid leukemia. 2854 Jul 46

Noncoding somatic mutations have been demonstrated to play important role in tumourigenesis. Here we show that there exists an acute myeloid leukaemia associated noncoding somatic mutation at 3' terminal of conserved HOXA cluster. The mutation was identified in the bone marrow blasts but not peripheral blood mononuclear cells or buccal cells of two M3 (acute promyelocytic leukaemia, APL) type patients from 45 acute myeloid leukaemia patients. The mutation also existed in a pair of twins one of them developed acute myeloid leukaemia M4 (acute myelomonocytic leukaemia) type. The mutation resides in about 2-kb downstream of HOXA1 gene where a functional retinoic acid response element is located and also bound by histone demethylase KDM3B. Reporter assay showed that the mutation results in the upregulation of transcriptional activity and unresponsiveness to retinoic acid receptor. To sum up, we identified a new acute myeloid leukaemia associated noncoding somatic mutation.
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PMID:Identification of an acute myeloid leukaemia associated noncoding somatic mutation at 3' end of HOXA cluster. 3120 14

Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI-4) and JDI-12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI-4 and JDI-12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI-4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI-4 and JDI-12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI-4 and JDI-12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI-16, among multiple compounds structurally akin to JDI-4/JDI-12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI-4/JDI-12. Mechanistically, JDI-16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI-16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI-16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI-16 collaborates with all-trans retinoic acid to repress MLLr AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells.
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PMID:Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells. 3127 62