Dataset Information

DAC for Pitteloud group

ABSTRACT: Data Access Committee EGAC00001000690

PROVIDER: EGAC00001000690 | EGA |

REPOSITORIES: EGA

ACCESS DATA

Publications

KLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.

Xu Cheng C Messina Andrea A Somm Emmanuel E Miraoui Hichem H Kinnunen Tarja T Acierno James J Niederländer Nicolas J NJ Bouilly Justine J Dwyer Andrew A AA Sidis Yisrael Y Cassatella Daniele D Sykiotis Gerasimos P GP Quinton Richard R De Geyter Christian C Dirlewanger Mirjam M Schwitzgebel Valérie V Cole Trevor R TR Toogood Andrew A AA Kirk Jeremy Mw JM Plummer Lacey L Albrecht Urs U Crowley William F WF Mohammadi Moosa M Tena-Sempere Manuel M Prevot Vincent V Pitteloud Nelly N

EMBO molecular medicine 20171001 10

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with β-Klotho (KLB), the obligate co ...[more]

PMID: 28754744

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Project description:Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitor, decitabine (5-aza-2'-deoxycitidine), is proving efficacious for hematological neoplasms especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response seen in patients. Transient exposure of leukemic and solid tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity or apoptosis, produces sustained reduced tumorigenicity, and for leukemia cells, diminished long-term self-renewal. These effects appear triggered by cellular reprogramming and include sustained decreases in promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, most of which are high priority targets for pharmacologic anti-cancer strategies. Thus, low dose decitabine regimens appear to have broad applicability for cancer management. [Gene expression profiling] Leukemia cell lines Kasumi-1 and KG1A are treated with 10nM DAC during 72 hours and gene expression was assayed at day 3, 7 and 14 after the start of the treatment. Appropriate mock treated samples were used as control in each case. In addition, Kasumi-1 cells were also treated with a higher dose of DAC (500nM), 100nM ARA-C and 300 nM TSA, again controlled against mock treated Kasumi-1 cells, to separate dose and agent dependent effects. MCF7 was studied as an example of a solid tumor cell line. Therefore MCF7 cells were treated with 100nM DAC and results were assayed at day 1, day 3 and day 10. [Methylation profiling] The effects of the demethylating agent DAC were studied in the leukemia cell line Kasumi-1 over a 28 day time course. Intermediate time points were studied at days 3, 7, 14 and 21. These results were verfied in KG1A and KG1 leukemia cell lines, at one selected time point. The effects on one primary sample were also studied. Four normal leukemia samples (PL1, 2, 4 and 5) were used as general controls. The effect of DAC was compared to ARA-C, TSA. Both mock treated and day 3 DAC treated Kasumi-1 cells were repeated. These results were verified at one selected time point for the DAC treated MCF7 breast cancer cell line.

Dataset Information

DAC for Pitteloud group

Publications

<i>KLB</i>, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.

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Dataset Information

DAC for Pitteloud group

Publications

&lt;i&gt;KLB&lt;/i&gt;, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

<i>KLB</i>, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism.