Hypoxia-Sensitive Epigenetic Regulation of an Antisense-Oriented lncRNA Controls WT1 Expression in Myeloid Leukemia Cells

McCarty, Gregory; Loeb, David M.

doi:10.1371/journal.pone.0119837

Cited by 60 publications

(48 citation statements)

References 35 publications

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“…Melanocytes are specialised cells that are responsible for the production of melanin, an important skin chromophore (Abdel-Malek et al, 2000;McCarty and Loeb, 2015;Ratajczak-Wrona et al, 2009). Normal skin physiology includes an epidermal-melanin unit, comprised of keratinocytes and melanocytes arranged at a ratio 35:1, the function of which is to produce melanin to protect keratinocytes from the harmful effects of environmental stressors Costin and Hearing, 2007).…”

Section: Keratinocytes and The Epidermal-melanin Unitmentioning

confidence: 99%

Heat stress: A risk factor for skin carcinogenesis

2013

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Section: Keratinocytes and The Epidermal-melanin Unitmentioning

confidence: 99%

Heat stress: A risk factor for skin carcinogenesis

2013

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“…As lncRNAs have emerged as important participants in the pathogenesis and disease progression of AML, [66][67][68][69][70][71][72][73][74] it is likely that profiling of their expression would have significant impact on MDS prognostication. Recently, it has been shown that lncRNA expression signatures were closely associated with specific mutations and a small subset of lncRNAs could predict clinical outcome in cytogenetically normal elderly AML patients, 75 but the clinical significance of lncRNA profiling in MDSs has not yet been reported.…”

Section: Discussionmentioning

confidence: 99%

A 4-lncRNA scoring system for prognostication of adult myelodysplastic syndromes

Yao

Chen

Huang³

et al. 2017

Blood Advances

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Key Points• Through lncRNA profiling, we identified an MDS patient subset with distinct clinical and mutational patterns along with inferior outcomes.• A concise yet powerful 4-lncRNA risk-scoring system was devised with the potential to improve current MDS risk stratification.Long noncoding RNAs (lncRNAs) not only participate in normal hematopoiesis but also contribute to the pathogenesis of acute leukemia. However, their clinical and prognostic relevance in myelodysplastic syndromes (MDSs) remains unclear to date. In this study, we profiled lncRNA expressions in 176 adult patients with primary MDS, and identified 4 lncRNAs whose expression levels were significantly associated with overall survival (OS). We then constructed a risk-scoring system with the weighted sum of these 4 lncRNAs. Higher lncRNA scores were associated with higher marrow blast percentages, higher-risk subtypes of MDSs (based on both the Revised International Prognostic Scoring System [IPSS-R] and WorldHealth Organization classification), complex cytogenetic changes, and mutations in RUNX1, ASXL1, TP53, SRSF2, and ZRSR2, whereas they were inversely correlated with SF3B1 mutation. Patients with higher lncRNA scores had a significantly shorter OS and a higher 5-year leukemic transformation rate compared with those with lower scores. The prognostic significance of our 4-lncRNA risk score could be validated in an independent MDS cohort. In multivariate analysis, higher lncRNA scores remained an independent unfavorable risk factor for OS (relative risk, 4.783; P , .001) irrespective of age, cytogenetics, IPSS-R, and gene mutations. To our knowledge, this is the first report to provide a lncRNA platform for risk stratification of MDS patients. In conclusion, our integrated 4-lncRNA risk-scoring system is correlated with distinctive clinical and biological features in MDS patients, and serves as an independent prognostic factor for survival and leukemic transformation. This concise yet powerful lncRNA-based scoring system holds the potential to improve the current risk stratification of MDS patients.

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“…Gene expression profiling of mRNA levels had been found to outperform the traditional parameters, such as morphology and cytogenetics, in prognostication of MDSs whether CD34 1 selected cells [62][63][64] or unsorted bulk marrow cells 65 were used for analysis. As lncRNAs have emerged as important participants in the pathogenesis and disease progression of AML, [66][67][68][69][70][71][72][73][74] it is likely that profiling of their expression would have significant impact on MDS prognostication. Recently, it has been shown that lncRNA expression signatures were closely associated with specific mutations and a small subset of lncRNAs could predict clinical outcome in cytogenetically normal elderly AML patients, 75 but the clinical significance of lncRNA profiling in MDSs has not yet been reported.…”

Section: Discussionmentioning

confidence: 99%

A 6-Lncrna Scoring System for Prognostication of Adult Myelodysplastic Syndromes

Yao

Chen

Huang

et al. 2016

Blood

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Background: Myelodysplastic syndromes (MDS) are highly heterogeneous regarding pathogenesis and clinical outcome. Traditionally, the revised international prognostic scoring system (IPSS-R)incorporating clinical features and cytogenetic abnormalities has been the standard for prognostication, while in recent years, recurrent somatic mutations are becoming increasingly important for this purpose. Additionally, gene expression profiling of coding genes and microRNAs has also emerged as a powerful tool to separate patients into distinct prognostic categories. Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides without protein-coding capacity. lncRNAs not only participate in normal hematopoiesis, but perturbation of their expressions may contribute to development of acute leukemia. However, the impact of lncRNA expression profiling on the prognosis of MDS patients has not yet been explored to date. Aims: This study was aimed to evaluate lncRNAs expression profiling in MDS and to find out lncRNAs whose expression levels were associated with clinical outcomes. A scoring system was constructed to better risk-stratify MDS patients. We also tried to seek clues to the functionality of these lncRNAs. Materials & Methods: By using the Affymetrix Human Transcriptome Array 2.0 platform, we obtained the global expression profiles of 24120 lncRNAs in 176 adult patients with de novo MDS diagnosed according to the 2008 WHO classification. Through mathematical modeling, we identified six lncRNAs whose expression levels were significantly associated with overall survival (OS). We then constructed a risk scoring system with the weighted sum of each of these six lncRNAs, and evaluated the correlation of the scores with clinical features,cytogenetic abnormalities, gene mutations, andtreatment outcomesof the MDS patients.The reliability of our lncRNA scoring system was assured based on the coefficient of variance obtained from a permutation test, and further validated by using a five-fold cross-validation, in which 80% of the patients were used as the training samples to develop the scoring model, whose prediction performances were evaluated by using the rest of the 20% of the patients. Analysis of mutations in 21 genes was performed by conventional Sanger sequencing technique. Results: Higher lncRNA scores were positively associated with refractory anemia with excess of blasts (RAEB)-1 or RAEB-2 subtypes, complex cytogenetic changes, and IPSS-R high and very high risks, but inversely associated with RCUD, RARS, RCMD subtypes, a normal karyotype, and IPSS-R low risk. Patients with higher lncRNA scores had more frequent RUNX1, ASXL1, TP53, EZH2, SRSF2 and ZRSR2 mutations, shorter OS (median 14.0 months vs. 77.3 months, P<0.001, Figure 1), and higher five-year leukemic transformation rate (72.0% vs. 17.9%, P<0.001), compared with those with lower lncRNA scores. The predictive power of this 6-lncRNA model was validated by a five-fold cross validation procedure. In multivariable analyses, a higher lncRNA score remained an independent unfavorable risk factor for OS (RR 2.428, 95% CI 1.751-3.367, P<0.001) after adjusting for other clinical and molecular variables. Moreover, the survival difference between higher-score and lower-score patients remained statistically significant in both IPSS-R higher-risk (high and very high risks) and lower-risk (very low, low and intermediate risks) subgroups (Figure 2). We also correlated our lncRNA score with mRNA expression profiling, and identified that higher lncRNA scores were associated with pathways related to acute myeloid leukemia and hematopoiesis. Conclusion: Our integrated 6-lncRNA risk scoring system provides distinct insights into the clinical and biological implications of lncRNAs expression in de novo MDS patients. The scoring system represents an independent prognostic factor for survival and leukemic transformation. It may assist improving risk stratification of newly-diagnosed MDS patients. Further prospective trials are necessary to confirm the findings of our study. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Hypoxia-Sensitive Epigenetic Regulation of an Antisense-Oriented lncRNA Controls WT1 Expression in Myeloid Leukemia Cells

Cited by 60 publications

References 35 publications

Heat stress: A risk factor for skin carcinogenesis

Heat stress: A risk factor for skin carcinogenesis

A 4-lncRNA scoring system for prognostication of adult myelodysplastic syndromes

A 6-Lncrna Scoring System for Prognostication of Adult Myelodysplastic Syndromes

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