Abstract 2766: DNA methylation status of MLH1, p16 and SOCS1 in Puerto Rican patients with acute myeloid leukemia

The DLK1–DIO3 region contains a large miRNA cluster, the overexpression of which has previously been associated with myelodysplastic syndromes (MDS). To reveal whether this overexpression is epigenetically regulated, we performed an integrative analysis of miRNA/mRNA expression and DNA methylation of the regulatory sequences in the region (promoter of the MEG3 gene) in CD34+ bone marrow cells from the patients with higher-risk MDS and acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), before and during hypomethylating therapy with azacytidine (AZA). Before treatment, 50% of patients showed significant miRNA/mRNA overexpression in conjunction with a diagnosis of AML-MRC. Importantly, increased level of MEG3 was associated with poor outcome. After AZA treatment, the expression levels were reduced and were closer to those seen in the healthy controls. In half of the patients, we observed significant hypermethylation in a region preceding the MEG3 gene that negatively correlated with expression. Interestingly, this hypermethylation (when found before treatment) was associated with longer progression-free survival after therapy initiation. However, neither expression nor methylation status were associated with future responsiveness to AZA treatment. In conclusion, we correlated expression and methylation changes in the DLK1–DIO3 region, and we propose a complex model for regulation of this region in myelodysplasia.

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Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse

Blood ◽

10.1182/blood-2007-11-126227 ◽

2008 ◽

Vol 112 (4) ◽

pp. 1366-1373 ◽

Cited By ~ 103

Author(s):

Heike Kroeger ◽

Jaroslav Jelinek ◽

Marcos R. H. Estécio ◽

Rong He ◽

Kimie Kondo ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cpg Island ◽

Methylation Status ◽

Cpg Islands ◽

Leukemia Cell ◽

Transcription Start Sites ◽

Remission Maintenance ◽

Acute Myeloid

AbstractDNA methylation of CpG islands around gene transcription start sites results in gene silencing and plays a role in leukemia pathophysiology. Its impact in leukemia progression is not fully understood. We performed genomewide screening for methylated CpG islands and identified 8 genes frequently methylated in leukemia cell lines and in patients with acute myeloid leukemia (AML): NOR1, CDH13, p15, NPM2, OLIG2, PGR, HIN1, and SLC26A4. We assessed the methylation status of these genes and of the repetitive element LINE-1 in 30 patients with AML, both at diagnosis and relapse. Abnormal methylation was found in 23% to 83% of patients at diagnosis and in 47% to 93% at relapse, with CDH13 being the most frequently methylated. We observed concordance in methylation of several genes, confirming the presence of a hypermethylator pathway in AML. DNA methylation levels increased at relapse in 25 of 30 (83%) patients with AML. These changes represent much larger epigenetic dysregulation, since methylation microarray analysis of 9008 autosomal genes in 4 patients showed hypermethylation ranging from 5.9% to 13.6% (median 8.3%) genes at diagnosis and 8.0% to 15.2% (median 10.6%) genes in relapse (P < .001). Our data suggest that DNA methylation is involved in AML progression and provide a rationale for the use of epigenetic agents in remission maintenance.

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A study on DNA methylation status in promoter region of p15 gene in patients of acute myeloid leukemia and myelodysplastic syndrome

Medical Journal Armed Forces India ◽

10.1016/j.mjafi.2021.04.014 ◽

2021 ◽

Author(s):

Sangeetha Sampath ◽

Pratibha Misra ◽

Sandeep Kumar Yadav ◽

Sanjeevan Sharma ◽

Venkatesan Somasundaram

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Promoter Region ◽

Myeloid Leukemia ◽

Methylation Status ◽

P15 Gene ◽

Acute Myeloid

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Abstract A92: Preliminary report on the methylation status of CDKN2A and MLH1 genes in Puerto Rican patients with acute myeloid leukemia

10.1158/1055-9965.disp-10-a92 ◽

2010 ◽

Author(s):

Maribel Tirado-Gomez ◽

Raul D. Bernabe-Dones ◽

Mercedes Y. Lacourt ◽

Cristina I. Castro-Munoz ◽

Maribel Cotto-Santiago

Keyword(s):

Acute Myeloid Leukemia ◽

Puerto Rican ◽

Myeloid Leukemia ◽

Preliminary Report ◽

Methylation Status ◽

Acute Myeloid

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Validation of DNA Methylation to Predict Outcome in Acute Myeloid Leukemia by Use of xMELP

Clinical Chemistry ◽

10.1373/clinchem.2014.229781 ◽

2015 ◽

Vol 61 (1) ◽

pp. 249-258 ◽

Cited By ~ 8

Author(s):

Gerald B W Wertheim ◽

Catherine Smith ◽

Marlise Luskin ◽

Alison Rager ◽

Maria E Figueroa ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Random Forest ◽

Myeloid Leukemia ◽

Clinical Laboratory ◽

Methylation Status ◽

Turnaround Time ◽

Random Forest Classifier ◽

Multiple Loci ◽

Acute Myeloid

Abstract BACKGROUND Epigenetic dysregulation involving alterations in DNA methylation is a hallmark of various types of cancer, including acute myeloid leukemia (AML). Although specific cancer types and clinical aggressiveness of tumors can be determined by DNA methylation status, the assessment of DNA methylation at multiple loci is not routinely performed in the clinical laboratory. METHODS We recently described a novel microsphere-based assay for multiplex evaluation of DNA methylation. In the current study, we validated and used an improved assay [termed expedited microsphere HpaII small fragment Enrichment by Ligation-mediated PCR (xMELP)] that can be performed with appropriate clinical turnaround time. RESULTS Using the xMELP assay in conjunction with a new 17-locus random forest classifier that has been trained using 344 AML samples, we were able to segregate an independent cohort of 70 primary AML patients into methylation-determined subgroups with significantly distinct mortality risk (P = 0.009). We also evaluated precision, QC parameters, and preanalytic variables of the xMELP assay and determined the sensitivity of the random forest classifier score to failure at 1 or more loci. CONCLUSIONS Our results demonstrate that xMELP performance is suitable for implementation in the clinical laboratory and predicts AML outcome in an independent patient cohort.

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Quantitative DNA methylation predicts survival in adult acute myeloid leukemia

Blood ◽

10.1182/blood-2009-03-211003 ◽

2010 ◽

Vol 115 (3) ◽

pp. 636-642 ◽

Cited By ~ 109

Author(s):

Lars Bullinger ◽

Mathias Ehrich ◽

Konstanze Döhner ◽

Richard F. Schlenk ◽

Hartmut Döhner ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Large Scale ◽

Methylation Status ◽

Multivariable Analysis ◽

Molecular Heterogeneity ◽

Prognostic Impact ◽

Outcome Predictor ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is characterized by molecular heterogeneity that is not fully reflected in the current classification system. Recent insights point toward a significant role of aberrant DNA methylation in leukemogenesis. Therefore, we investigated the prognostic impact of DNA methylation in AML. To screen for promoter methylation in AML we applied a combination of base-specific cleavage biochemistry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), a powerful methodology allowing for quantitatively investigating DNA methylation status in a large series of both promoter regions and leukemia samples. We analyzed 92 genomic regions in 182 patient samples, correlated findings with clinical and molecular data, and validated the results in an independent cohort of 74 AML samples. Using this approach, we were able to identify novel leukemia subgroups based on distinct DNA methylation patterns. Furthermore, we defined a methylation-based outcome predictor for patient survival (P < .01) that in multivariable analysis provided independent prognostic information (hazard ratio, 1.52; 95% CI, 1.06-2.16). Here, we report the first large-scale methylation-based outcome predictor in AML, and thereby our findings support the use of genomic methylation markers for improved molecular classification and prognostication in adult AML.

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Faculty Opinions recommendation of DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1528964.1017064 ◽

2010 ◽

Author(s):

Lee Grimes

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Acute Myeloid

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Identification and validation of obesity-related gene LEP methylation as a prognostic indicator in patients with acute myeloid leukemia

Clinical Epigenetics ◽

10.1186/s13148-021-01013-9 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Ting-juan Zhang ◽

Zi-jun Xu ◽

Yu Gu ◽

Ji-chun Ma ◽

Xiang-mei Wen ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Indicator ◽

The Cancer Genome Atlas ◽

Related Gene ◽

Targeted Bisulfite Sequencing ◽

Specific Pcr ◽

Frequent Event ◽

Acute Myeloid

Abstract Background Obesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated. Results In the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML. Conclusions Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.

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