Downregulation of circadian clock genes in chronic myeloid leukemia: Alternative methylation pattern of <i>hPER3</i>

Yang, Mingyu; Chang, Jan‐Gowth; Lin, Pei; Tang, Kai-Ping; Chen, Yen-Hsu; Lin, Hugo You-Hsien; Liu, Ta-Chih; Hsiao, Hui‐Hua; Liu, Yi-Chang; Lin, Sheng-Fuu

doi:10.1111/j.1349-7006.2006.00331.x

Cited by 114 publications

(102 citation statements)

References 42 publications

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“…22 A cyclic and significant expression of circadian clock genes in peripheral mononuclear blood cells of healthy individuals 23 and an anomalous expression of CRY1 (among other components of the biological clock) has been documented during chronic and blastic phases of chronic myeloid leukemia. 24 In our study, CRY1 show a similar or better behavior than other well established biomarkers in CLL, such as ZAP70, CD38, LPL or cytogenetic abnormalities, and an excellent correlation with IgVH mutational status. Our observation, along with the easiness of CRY1 determination by RTqPCR on B lymphocytes or unselected PBMC, indicate that CRY1 may be used as a new marker of disease progression for the initial prognostic assessment of early-stage CLL.…”

mentioning

confidence: 77%

Cryptochrome-1 expression: a new prognostic marker in B-cell chronic lymphocytic leukemia

Jantus‐Lewintre¹,

Martín²,

Ballesteros³

et al. 2009

Haematologica

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The objective of this study was to evaluate the prognostic significance of CRY1 expression in early-stage CLL, and its relationship with other well established prognostic markers in CLL. Design and Methods Chronic lymphocytic leukemia patients and samplesSeventy samples from previously untreated CLL patients (Binet stage A) were included in this study after informed consent was obtained. Clinical diagnosis was based on standard morphological and immunophenotypic criteria. Definition of progressive disease was based on the NCI guidelines. 15 Mononuclear cells (PBMC) were isolated from peripheral blood by Ficoll-Hypaque (Lymphoprep™) density centrifugation. Samples were then processed for CD19 + selection, FC analysis and DNA/RNA isolation. Analysis of IgVH somatic mutation statusDNA was prepared using a standard protocol and IgVH gene rearrangements were performed using BIO-MED-2 primers. 16 We considered unmutated those samples with ≥98% homology with the closest germinal line. RTqPCR assayscDNA was synthesized from 1.5 µg of total RNA using random hexanucleotides and SuperScriptII (Invitrogen) following the manufacturer's instructions. RTqPCR assays were carried out using "Hs00172734-m1 (CRY1), Hs00277148-m1 (ZAP70) and Hs00173425-m1 (LPL) primers and probe sets (TaqMan ® Gene Expression Assays, Applied Biosystems). Amplification of GUS gene was performed in all cases to normalize gene expression. Interphase fluorescence in situ hybridization (FISH)A panel of commercially available probes (Vysis) was used to target chromosomes 11q22.3 (ATM), 13q14 (D13S25 and D13S319), 17p13 (TP53) deletions and trisomy 12 on blood smears according to a standard protocol. ZAP70 flow cytometry assayIntracellular ZAP-70 expression was analyzed in 69 samples by FC according to Crespo et al. 17 with some modifications. We use an isotype control as negative control. Results ≥20% were considered positive. Statistical analysisSignificant differences between groups were assessed by the Mann-Whitney test and considered significant when p values <0.05. All statistical calculations were performed using the SPSS 13.0 software. Progression free survival (PFS) was calculated from the date of diagnosis to disease progression or last followup. For more detailed information see the Online Supplementary Appendix. Results and Discussion CRY1 expression and IgVH mutational statusOut of the 70 Binet's stage A patients tested for IgVH mutational status, 50 were mutated in IgVH genes (71.4%). These percentages are slightly different from those reported in previous studies 6,18,19 because in most of them, patients with different stages of the disease were included.To assess the usefulness of CRY1 expression as surrogate marker for IgVH mutational status, we determined CRY1 by RTqPCR in CD19 + cell samples. The mean ± 2 SEM relative concentration in unmutated and mutated samples were: 0.311±0.081 and 0.034±0.023, respectively, p<0.0001 (Online Supplementary Figure S1).The optimal predictive model based on CRY1 expression in relation to IgVH mutationa...

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mentioning

confidence: 77%

Cryptochrome-1 expression: a new prognostic marker in B-cell chronic lymphocytic leukemia

Jantus‐Lewintre¹,

Martín²,

Ballesteros³

et al. 2009

Haematologica

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“…[14][15][16][17] Abnormalities in Period promoter methylation and histone acetylation status have also been reported in human tumors. 18 Therefore, both genetic and epigenetic changes in Period genes are found in human tumors. Overexpression of Per1 or Per2 also inhibits cancer cell proliferation and clonogenicity.…”

Section: Period Genes and Cancermentioning

confidence: 99%

Clock Genes and Cancer

2009

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Period genes (Per2, Per1) are essential circadian clock genes. They also function as negative growth regulators. Per2 mutant mice show de novo and radiation-induced epithelial hyperplasia, tumors, and an abnormal DNA damage response. Human tumors show Period gene mutations or decreased expression. Other murine clock gene mutations are not associated with a tumor prone phenotype. Shift work and nocturnal light exposure are associated with circadian clock disruption and with increased cancer risk. The mechanisms responsible for the connection between the circadian clock and cancer are not well defined. We propose that circadian disruption per se is not uniformly tumor promoting and the mechanisms for tumor promotion by specific circadian clock disturbances will differ dependent upon the genes and pathways involved. We propose that Period clock gene mutations promote tumorigenesis by unique molecular pathways. Per2 and Per1 modulate β-catenin and cell proliferation in colon and non-colon cancer cells. Per2 mutation increases intestinal β-catenin levels and colon polyp formation. Per2 mutation also increases Apc Min/+ -mediated intestinal and colonic polyp formation. Intestinal tumorigenesis per se may also alter clock function as a result of increased β-catenin destabilizing PER2 protein. Levels and circadian rhythm of PER2 in Apc Min/+ mouse intestine are markedly decreased, and selective abnormalities in intestinal clock gene and clock-controlled gene expression are seen. We propose that tumor promotion by loss of PERIOD clock proteins is unique to these clock genes as a result of altered β-catenin signaling and DNA damage response. PERIOD proteins may offer new targets for cancer prevention and control.

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“…27 In fact, it was shown that several circadian clock genes can be transcriptionally silenced by promoter hypermethylation in different malignancies and that a clear correlation exists between methylation frequency and the clinical phases of diseases. [28][29][30] The NPAS2 gene promoter specifically is hypomethylated in Parkinson's disease patients, leading to the suggestion that altered promoter methylation may contribute to abnormal expression of clock genes in this disease. 31 We suggest a possible correlation between promoter regulation and NPAS2 deregulation in melanoma, although this postulate requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

A polymorphic GGC repeat in the NPAS2 gene and its association with melanoma

Franzoni

Markova-Car

Pavlić

et al. 2017

Exp Biol Med (Maywood)

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This report describes a variable microsatellite repeat sequence located in the 5 0 untranslated exon of NSPAS2, a gene encoding a clock transcription factor. Significantly, this study is the first to show that a variant copy number GGC repeat sequence in the NPAS2 clock gene associates with melanoma risk and which may be useful in the assessment of melanoma predisposition. AbstractCircadian clock regulation in mammals is controlled by feedback loops of a set of circadian genes. One of these circadian genes, NPAS2, encodes for a member of the bHLH-PAS class of transcription factors and is expressed in the forebrain and in some peripheral organs such as liver and skin. Other biological processes are also regulated by circadian genes. For example, NPAS2 is involved in cell proliferation, DNA damage repair and malignant transformation. Aberrant expression of clock genes has been previously observed in melanoma which led to our effort to sequence the NPAS2 promoter region in this cancer type. The NPAS2 putative promoter and 5 0 untranslated region of ninety-three melanoma patients and ninety-six control subjects were sequenced and several variants were identified. Among these is a novel microsatellite comprising a GGC repeat with different alleles ranging from 7 to 13 repeats located in the 5 0 untranslated exon. Homozygosity of an allele with nine repeats (9/9) was more prevalent in melanoma than in control subjects (22.6% and 13.5%, respectively, P: 0.0206) suggesting that some NPAS2 variants might contribute to melanoma susceptibility.

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Downregulation of circadian clock genes in chronic myeloid leukemia: Alternative methylation pattern of hPER3

Cited by 114 publications

References 42 publications

Cryptochrome-1 expression: a new prognostic marker in B-cell chronic lymphocytic leukemia

Cryptochrome-1 expression: a new prognostic marker in B-cell chronic lymphocytic leukemia

Clock Genes and Cancer

A polymorphic GGC repeat in the NPAS2 gene and its association with melanoma

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