scholarly journals Genetic characteristics and prognosis of m6A RNAmethylation regulator in acute myeloid leukemia

2020 ◽  
Author(s):  
Jiasheng Xu ◽  
Kaili Liao ◽  
Zhonghua Fu ◽  
Zhenfang Xiong
Keyword(s):  
Myeloid Leukemia ◽  
Gene Annotation ◽  
Clinicopathological Characteristics ◽  
Risk Scores ◽  
Genetic Characteristics ◽  
Rna Methylation ◽  
Pathological Characteristics ◽  
Potential Value ◽  
M6a Rna Methylation ◽  
Acute Myeloid

Abstract Background: To identify the genetic characteristics of m6A RNA methylation regulators in AML and explore their potential value as prognostic markers.Methods: RNA-seq transcriptome data and clinical survival data of acute myeloid leukemia (AML) were downloaded from ICGC and TCGA, gene annotation files were downloaded from GENECODE (1). 13 widely reported m6A RNA alphas were obtained from the literature. The expression of m6A RNA methylation regulators were collected and analized using gene annotation files. The samples were subjected to consistent clustering to obtain two subgroups RM1 and RM2, and the pathological characteristics and survival between the two subgroups were analyzed. Comparative analysis and functional analysis of m6A RNA methylation regulators between subgroups were completed. The STRING database analyzed the interactions between m6A RNA methylation regulators, and Spearman analyzed the correlation of expression of m6A RNA methylation regulators. COX regression analysis and risk scores were used to predict prognosis and pathological characteristics, and risk scores calculated using features were used to predict the prognosis and clinicopathological characteristics of tumor patients.Results: According to the morphological characteristics of AML, the samples were divided into 8 categories (M0 Undifferentiated, M1, M2, M3, M4, M5, M6, M7), and among them, the expression profile and expression heat map of 13 m6A RNA methylation regulators were constructed. Using m6A RNA methylation regulator as a feature vector, consistent clustering of 151 samples yielded two subgroups RM1 and RM2. Among them, the expression of the regulator in RM1 was higher than RM2,and RM2 patients had a longer survival time than RM1. Gene set enrichment analysis found that functional processes such as endothelial-hematopoietic transformation through the Notch pathway were significantly enriched in RM1. The analysis of the KM curve indicates that when the expression of FTO or ALKBH5 or of ZC3H13 was low, the survival time of patients was significantly higher than that with high expression.Conclusion: m6A RNA methylase regulator is not only an independent prognostic marker of AML, but also can predict its clinicopathological characteristics, which has potential value for stratifying prognosis and improving treatment strategies.

Pattern of Central Nervous System (CNS) Involvement in Adult Acute Myeloid Leukemia (AML) and Its Impact on Outcome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2789-2789
Author(s):  
Maria Ilaria Del Principe ◽  
Francesco Buccisano ◽  
Stefano Soddu ◽  
Luca Maurillo ◽  
Mariagiovanna Cefalo ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Newly Diagnosed ◽  
Cns Involvement ◽  
Genetic Characteristics ◽  
Cns Disease ◽  
The Impact ◽  
Acute Myeloid

Abstract Background Routine diagnostic lumbar puncture is not recommended in adult patients with acute myeloid leukemia (AML) without Central Nervous System (CNS) symptoms and little is known about the incidence of CNS involvement and its impact on survival in these patients. Furthermore, several studies have demonstrated that flow cytometry (FCM) is superior to conventional cytology (CC) for detection of CNS involvement in lymphoproliferative disorders but the role of this approach for the investigation of cerebrospinal fluid (CSF) in AML is unknown. Design and Methods The aims of our study were 1) to determine the incidence of occult/manifest CNS disease in a homogenous series of AML patients; 2) to correlate CNS disease with clinico-biologic parameters; 3) to examine the impact of CNS involvement on outcome. CSF samples were collected from 98 newly diagnosed AML patients, 62 males and 36 females, median age 53 years (range 18-75). Sixty-five and 33 patients aged <60 and>60 years, respectively.Seventy-one patients received standard and 22 high-dose-ARA-C-based regimens, 5 supportive care. All of 98 CSF samples were examined by CC whereas 90 (91%) also by FCM. CC positivity was defined as unequivocal morphologic evidence of leukemic blast in CSF and/or white blood cells count (WBCc) ≥ 5/µl with less than 10 erythrocytes/µl. A cluster of at least 10 phenotypically abnormal events was regarded as a proof of FCM positivity. Results Sixty-seven patients were CNS negative (CNS-) while thirty-one (31%) were CNS positive (CNS+). Among the last, 10 (10%) were positive on both CC and FCM (manifest CNS+) and 21 (21%) only on FCM (occult CNS+). There was an equal male/female distribution among CNS- and CNS+ patients, as well as median age (52 years, range, 20-71, vs 56 years, range, 18-75, p=NS) and WBCc(27.5 x109/L, range, 1,20-223 x109/L, vs. 11,6 x109/L, range, 0,70-315 x109/L, p= NS) were similar in both groups. Instead, higher levels of lactate dehydrogenase (LDH) were observed among CNS+ than CNS- patients (p=. 01). Forty-seven patients (48%) had monoblastic/monocytic or myelomonocytic AML and belonging to one of these categories was significantly associated with a condition of CNS positivity (55% vs 45%, P = 002). Cytogenetic/genetic data were available in 82/98 (84%). Twenty-for patients (29%), 33 (39%), 12 (14%) and 12 (14%), belonged to the category of favorable, intermediate-I, intermediate-II, and adverse karyotype, respectively. Cytogenetic/genetic characteristics did not differed significantly between CNS+ and CNS- patients. Overall, response rate was 70%, with complete remission rate being not statistically different between CNS+ and CNS- patients (69% vs 81% p= NS). Five-year DFS and OS were found to be significantly shorter in occult or manifest CNS+ patients than in those CNS- (23% vs 50% p= .03 and 19% vs 46%, p=.02, respectively)(Figure 1A and 1B). The prognostic variables achieving a statistical significance in univariate analysis (CNS status, age , WBCc, favorable vs adverse karyotype) were challenged in a multivariate model to determine to what extent they affected treatment outcome. In multivariate analysis, CNS positivity was found to be independently and significantly associated with a shorter duration of DFS.(p=.03 HR= 0.46). Age >50 years was found to be the only independent prognostic factor affecting OS (p=.01 HR= 2.26). Conclusion Our data suggest that incidence of CNS involvement in newly diagnosed AML pts is higher than expected. Regardless of neurologic symptoms, manifest and occult CNS positivity should always be sought at diagnosis since it may affect outcome and influence therapeutic decision. Further prospective studies on larger series are warranted to confirm this data. Figure 1 DFS and OS based on CNS status Figure 1. DFS and OS based on CNS status Disclosures Lo Coco: Teva: Consultancy, Honoraria, Speakers Bureau; Lundbeck: Honoraria, Speakers Bureau; Novartis: Consultancy; Baxalta: Consultancy; Pfizer: Consultancy.

scholarly journals Identification of a Prognostic Gene Signature Associated with Microenvironment in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Zhixiang Chen ◽  
Luya Ye ◽  
Xuechun Wang ◽  
Fuquan Tu ◽  
Xuezhen Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Critical Role ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Risk Scores ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is a common hematologic malignancy with poor prognosis. Accumulating reports have indicated that the tumor microenvironment (TME) performs a critical role in the progress of the disease and the clinical outcomes of patients. To date, the role of TME in AML remains clouded due to the complex regulatory mechanisms in it. In this study, We identified key prognostic genes relate to TME in AML and developed a novel gene signature for individualized prognosis assessment. Methods: The expression profiles of AML samples with clinical information were obtained from the Cancer Genome Atlas (TCGA). The ESTIMATE algorithm was applied to calculate the TME relevant immune and stromal scores. The differentially expressed genes (DEGs) were selected based on the immune and stromal scores. Then, the survival analysis was applied to select prognostic DEGs, and these genes were annotated by functional enrichment analysis. A TME relevant gene signature with predictive capability was constructed by a series of regression analyses and performed well in another cohort from the Gene Expression Omnibus (GEO) database. Moreover, we also developed a nomogram with the integration of the gene signature and clinical indicators to establish an individually quantified risk-scoring system. Results: In the AML microenvironment, a total of 181 DEGs with prognostic value were clarified. Then a seven-gene ( IL1R2, MX1, S100A4, GNGT2, ZSCAN23, PLXNB1 and DPY19L2 ) signature with robust prediction was identified, and was validated by an independent cohort of AML samples from the GSE71014. Gene set enrichment analysis (GSEA) of genes in the gene signature revealed these genes mainly enriched in the immune and inflammatory related processes. The correlation between the signature-calculated risk scores and the clinical features indicated that patients with high risk scores were accompanied by adverse survival. Finally, a nomogram with clinical utility was constructed. Conclusion: Our study explored and identified a novel TME relevant seven-gene signature, which could serve as a prognostic indicator for AML. Meanwhile, we also establish a nomogram with clinical significance. These findings might provide new insights into the diagnosis, treatment and prognosis of AML.

scholarly journals Prognostic Value of Genetic Alterations in Elderly Patients with Acute Myeloid Leukemia: A Single Institution Experience

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 570 ◽  
Author(s):  
Maël Heiblig ◽  
Hélène Labussière-Wallet ◽  
Franck Emmanuel Nicolini ◽  
Mauricette Michallet ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Statistical Significance ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Treatment Intensity ◽  
Intensive Chemotherapy ◽  
Genetic Characteristics ◽  
Acute Myeloid

Although the outcome in younger adults with acute myeloid leukemia (AML) has improved, the benefit associated with standard intensive chemotherapy in older patients remains debatable. In this study, we investigated the incidence and the prognostic significance of genetic characteristics according to treatment intensity in patients aged 60 years or older. On the 495 patients of our cohort, DNMT3A R882 (25.2%), NPM1 (23.7%) and FLT3-ITD (16.8%) were the most frequent molecular mutations found at diagnosis. In this elderly population, intensive chemotherapy seemed to be a suitable option in terms of early death and survival, except for normal karyotype (NK) NPM1−FLT3-ITD+ patients and those aged over 70 within the adverse cytogenetic/molecular risk group. The FLT3-ITD mutation was systematically associated with an unfavorable outcome, independently of the ratio. NK NPM1+/FLT3-TKD+ genotype tends to confer a good prognosis in patients treated intensively. Regarding minimal residual disease prognostic value, overall survival was significantly better for patients achieving a 4 log NPM1 reduction (median OS: 24.4 vs. 12.8 months, p = 0.013) but did not reach statistical significance for progression free survival. This retrospective study highlights that intensive chemotherapy may not be the most appropriate option for each elderly patient and that molecular markers may help treatment intensity decision-making.

scholarly journals Inflammation-related genes S100s, RNASE3, and CYBB and risk of leukemic transformation in patients with myelodysplastic syndrome with myelofibrosis

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Minghua Hong ◽  
Junqing Wu ◽  
Lifeng Ma ◽  
Xiaoping Han ◽  
Ting Lu ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemic Transformation ◽  
Genetic Characteristics ◽  
Expression Levels ◽  
Single Cell Sequencing ◽  
Before And After ◽  
Gene Expression Levels ◽  
Acute Myeloid

AbstractMyelodysplastic syndrome with myelofibrosis (MDS-MF) has been associated with an inferior prognosis compared with MDS without MF. However, MDS-MF is not listed independently as a subtype of MDS, and its clinical and genetic characteristics remain poorly understood. We retrospectively compared 53 patients with MDS-MF (44 MF grade 1/MF1; 9 MF grade 2–3/MF2 − 3) and 31 with de novo MDS without MF (MDS). The leukemic transformation risks of both MDS-MF2 − 3 and MDS-MF1 were increased compared with the MDS group. To identify the potential mechanisms responsible for the leukemic transformation of MDS-MF, we performed single-cell sequencing for one MDS-MF2 − 3 patient before and after leukemic transformation to explore the variations in gene expression levels. In addition to upgraded expression levels of acute myeloid leukemia-related genes during leukemic transformation, expression levels of some inflammation-related genes (such as S100s, RNASE3, and CYBB) were also increased, and inflammation-related pathways were up-regulated. These results suggest that inflammation-related genes and pathways may play an important role in the leukemic transformation of MDS-MF.

scholarly journals m6A-Related lncRNAs Affect Tumor Immune Microenvironment And Prognosis In Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Fangmin Zhong ◽  
Fangyi Yao ◽  
Ying Cheng ◽  
Jing Liu ◽  
Nan Zhang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Risk Scores ◽  
In Vitro Assays ◽  
Immune Microenvironment ◽  
Cox Regression Analysis ◽  
Tumor Immune Microenvironment ◽  
The Relationship ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a complex hematologic malignancy. Survival rate of AML patients is low. N6-methyladenosine (m6A) and long-chain non-coding RNAs (lncRNAs) play important roles in AML tumorigenesis and progression. However, the relationship between lncRNAs and biological characteristics of AML, as well as how lncRNAs influence the prognosis of AML patients, remain unclear. In this study, we identified m6A-related lncRNAs, and analyzed their roles and prognostic values in AML. m6A-related lncRNAs associated with patient prognosis were screened using univariate Cox regression analysis, followed by systematic analysis of the relationship between these genes and AML clinicopathologic and biologic characteristics. Furthermore, we examined the characteristics of tumor immune microenvironment (TIME) using different IncRNA clustering models. Using LASSO regression, we identified the risk signals related to prognosis of AML patients. We then constructed and verified a risk model based on m6A-related lncRNAs for independent prediction of overall survival in AML patients. Our results indicate that risk scores, calculated based on risk-related signaling, were related to the clinicopathologic characteristics of AML and level of immune infiltration. Finally, we examined the expression level of TRAF3IP2-AS1 in patient samples through real-time polymerase chain reaction analysis and in GEO datasets, and we identified SRSF10 as a regulator of TRAF3IP2-AS1 through in vitro assays. Our study shows that m6A-related lncRNAs, evaluated using the risk prediction model, can potentially be used to predict prognosis and design immunotherapy in AML patients.

scholarly journals Development and Validation of an m6A RNA Methylation Regulators-Based Signature for Predicting the Prognosis of Adrenocortical Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengquan Shen ◽  
Jing Liu ◽  
Xiaokun Yang ◽  
Wei Jiao ◽  
Yonghua Wang
Keyword(s):  
Survival Analysis ◽  
Prognostic Factor ◽  
Adrenocortical Carcinoma ◽  
Cox Regression ◽  
Independent Prognostic Factor ◽  
The Cancer Genome Atlas ◽  
Risk Scores ◽  
Predictive Values ◽  
Rna Methylation ◽  
M6a Rna Methylation

BackgroundAdrenocortical carcinoma (ACC) is an aggressive and rare neoplasm that originates from the cortex of the adrenal gland. N6-methyladenosine (m6A) RNA methylation, the most common form of mRNA modification, has been reported to be correlated with the occurrence and development of the malignant tumor. This study aims to identify the significance of m6A RNA methylation regulators in ACC and construct a m6A based signature to predict the prognosis of ACC patients.Materials and methodsRNA-seq data from The Cancer Genome Atlas (TCGA) database was used to identify the expression level of m6A RNA methylation regulators in ACC. An m6A based signature was further constructed and its prognostic and predictive values were assessed by survival analysis and nomogram.Results11 m6A RNA regulators were differentially expressed in ACC and three m6A RNA regulators were finally selected in a signature to predict the prognosis of ACC patients. Survival analysis indicated that high risk scores were closely related to poor survival outcomes in ACC patients. Univariate and multivariate Cox regression analyses demonstrated that the m6A based signature was an independent prognostic factor for ACC patients. A nomogram with clinical factors and the m6A based signature was also constructed to superiorly predict the prognosis of ACC patients. The expression levels of m6A RNA methylation regulators, which were contained in the signature, were also verified in human ACC tissues and normal tissues by using vitro experiments.ConclusionWe identified and validated an m6A based signature, which can be used as an independent prognostic factor in evaluating the prognosis of ACC patients. Further clinical trials and experimental explorations are needed to confirm our observations and mechanisms underlying prognostic values of these m6A RNA methylation regulators in ACC.

scholarly journals Identification of the 7-lncRNA Signature as a Prognostic Biomarker for Acute Myeloid Leukemia

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Chun-yu Liu ◽  
Hui-hui Guo ◽  
Hai-xia Li ◽  
Ying Liang ◽  
Cong Tang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Cox Regression ◽  
Cumulative Risk ◽  
Risk Scores ◽  
Sequencing Data ◽  
The Public ◽  
Target Database ◽  
Acute Myeloid

A lot of evidence has emphasized the function of long noncoding RNAs (lncRNAs) in tumors’ development and progression. Nevertheless, there is still a lack of lncRNA biomarkers that can predict the prognosis of acute myeloid leukemia (AML). Our goal was to develop a lncRNA marker with prognostic value for the survival of AML. AML patients’ RNA sequencing data as well as clinical characteristics were obtained from the public TARGET database. Then, differentially expressed lncRNAs were identified in female and male AML samples. By adopting univariate and multivariate Cox regression analyses, AML patients’ survival was predicted by a seven-lncRNA signature. It was found that 95 abnormal expressed lncRNAs existed in AML. Then, the analysis of multivariate Cox regression showed that, among them, 7 (LINC00461, RP11-309M23.1, AC016735.2, RP11-61I13.3, KIAA0087, RORB-AS1, and AC012354.6) had an obvious prognostic value, and according to their cumulative risk scores, these 7 lncRNA signatures could independently predict the AML patients’ overall survival. Overall, the prognosis of AML patients could be predicted by a reliable tool, that is, seven-lncRNA prognostic signature.

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