High Expression of CLEC11A Predicts Favorable Prognosis in Acute Myeloid Leukemia

BackgroundAcute myeloid leukemia (AML) is a heterogeneous disease of the hematopoietic system, for which identification of novel molecular markers is potentially important for clinical prognosis and is an urgent need for treatment optimization.MethodsWe selected C-type lectin domain family 11, member A (CLEC11A) for study via several public databases, comparing expression among a variety of tumors and normal samples as well as different organs and tissues. To investigated the relationship between CLEC11A expression and clinical characteristics, we derived an AML cohort from The Cancer Genome Atlas (TCGA); we also investigated the Bloodspot and HemaExplorer databases. The Kaplan-Meier method and log-rank test were used to evaluate the associations between CLEC11A mRNA expression, as well as DNA methylation, and overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS). DNA methylation levels of CLEC11A from our own 28 de novo AML patients were assessed and related to chemotherapeutic outcomes. Bioinformatics analysis of CLEC11A was carried out using public databases.ResultsMultiple public databases revealed that CLEC11A expression was higher in leukemia. The TCGA data revealed that high CLEC11A expression was linked with favorable prognosis (OS p-value = 2e-04; EFS p-value = 6e-04), which was validated in GSE6891 (OS p-value = 0; EFS p-value = 0; RFS p-value = 2e-03). Methylation of CLEC11A was negatively associated with CLEC11A expression, and high CLEC11A methylation level group was linked to poorer prognosis (OS p-value = 1e-02; EFS p-value = 2e-02). Meanwhile, CLEC11A hypermethylation was associated with poor induction remission rate and dismal survival. Bioinformatic analysis also showed that CLEC11A was an up-regulated gene in leukemogenesis.ConclusionCLEC11A may be used as a prognostic biomarker, and could do benefit for AML patients by providing precise treatment indications, and its unique gene pattern should aid in further understanding the heterogeneous AML mechanisms.

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Prognostic role and treatment tips of FHL1 expression in cytogenetically intermediate- and poor-risk acute myeloid leukemia

10.21203/rs.3.rs-17167/v1 ◽

2020 ◽

Author(s):

chengliang yin ◽

Yuchen Liu ◽

Qi Chen ◽

Min Zhao ◽

Jing Wu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Significance ◽

Rank Test ◽

Signal Pathways ◽

Drug Resistant ◽

Free Survival ◽

Poor Risk ◽

Treatment Indications ◽

Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is a heterogeneous disorder of hematopoietic system, 35 to 40% of younger patients (<60 years) are recurrent, refractory or drug-resistant, which are canonically called as cytogenetically intermediate- and poor-risk AML (IP-AML). Identifying novel biomarkers is an urgent clinical need and research hotspot for treatment optimization. Methods: Bioinformatics analysis were carried out for RNA-Seq data derived from drug resistance-associated cell lines and The Cancer Genome Atlas (TCGA). Varieties of comparison, visualization and functional enrichments were performed to Four-and-a-half LIM domain 1 (FHL1) and related genes. FHL1's expression changes were confirmed by ‘wet’ experiments. Kaplan-Meier method, log-rank test and multivariate Cox proportional hazards models were utilized to evaluate the associations between FHL1 expression and Overall Survival (OS), Event Free Survival (EFS), Relapse Free Survival (RFS). Prognostic significance of FHL1 expression was further validated in another independent larger IP-AML cohort (GSE6891). Moreover, construction of nomogram and validation of prognostic model. Results: High expression of FHL1 (FHL1 high ) was a potentially effective biomarker of poor prognosis for IP-AML. Compared to FHL1 low group, FHL1 high was associated with short OS and EFS (145 patients, OS, P < 0.001; EFS, P < 0.001), which was further validated in GSE6891 (284 patients, OS, P < 0.001; EFS, P < 0.001). Multivariate analysis also confirmed the adverse prognosis of FHL1 high (HR = 2.2339, P = 0.000156). ROC indicated an ideal predictive accuracy of the outcome model (AUC was 0.773). In addition, to understand the inherent mechanisms FHL1 involved, genome-wide characteristics were investigated to find that FHL1 might be involved in several important carcinogenic signal pathways. Conclusions: FHL1’s expression may serve as an effective prognostic biomarker, and could provide valuable treatment indications for IP-AML patients, whose distinctive gene patterns were helpful to further understand the recurrent, refractory and drug-resistant mechanisms for IP-AML.

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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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Genome-wide regulation of CpG methylation by ecCEBPα in acute myeloid leukemia

F1000Research ◽

10.12688/f1000research.28146.1 ◽

2021 ◽

Vol 10 ◽

pp. 204

Author(s):

Adewale J. Ogunleye ◽

Ekaterina Romanova ◽

Yulia A. Medvedeva

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cpg Methylation ◽

The Cancer Genome Atlas ◽

Binding Potential ◽

Hematopoietic Malignancy ◽

Genome Wide ◽

A Genome ◽

Acute Myeloid

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by genetic and epigenetic aberrations that alter the differentiation capacity of myeloid progenitor cells. The transcription factor CEBPα is frequently mutated in AML patients leading to an increase in DNA methylation in many genomic locations. Previously, it has been shown that ecCEBPα (extra coding CEBPα) - a lncRNA transcribed in the same direction as CEBPα gene - regulates DNA methylation of CEBPα promoter in cis. Here, we hypothesize that ecCEBPα could participate in the regulation of DNA methylation in trans. Method: First, we retrieved the methylation profile of AML patients with mutated CEBPα locus from The Cancer Genome Atlas (TCGA). We then predicted the ecCEBPα secondary structure in order to check the potential of ecCEBPα to form triplexes around CpG loci and checked if triplex formation influenced CpG methylation, genome-wide. Results: Using DNA methylation profiles of AML patients with a mutated CEBPα locus, we show that ecCEBPα could interact with DNA by forming DNA:RNA triple helices and protect regions near its binding sites from global DNA methylation. Further analysis revealed that triplex-forming oligonucleotides in ecCEBPα are structurally unpaired supporting the DNA-binding potential of these regions. ecCEBPα triplexes supported with the RNA-chromatin co-localization data are located in the promoters of leukemia-linked transcriptional factors such as MLF2. Discussion: Overall, these results suggest a novel regulatory mechanism for ecCEBPα as a genome-wide epigenetic modulator through triple-helix formation which may provide a foundation for sequence-specific engineering of RNA for regulating methylation of specific genes.

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Genome-wide regulation of CpG methylation by ecCEBPα in acute myeloid leukemia

F1000Research ◽

10.12688/f1000research.28146.2 ◽

2021 ◽

Vol 10 ◽

pp. 204

Author(s):

Adewale J. Ogunleye ◽

Ekaterina Romanova ◽

Yulia A. Medvedeva

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cpg Methylation ◽

The Cancer Genome Atlas ◽

Binding Potential ◽

Hematopoietic Malignancy ◽

Genome Wide ◽

A Genome ◽

Acute Myeloid

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Improved Treatment Results in High-Risk Pediatric Acute Myeloid Leukemia Patients After Intensification With High-Dose Cytarabine and Mitoxantrone: Results of Study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster 93

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.10.2705 ◽

2001 ◽

Vol 19 (10) ◽

pp. 2705-2713 ◽

Cited By ~ 143

Author(s):

U. Creutzig ◽

J. Ritter ◽

M. Zimmermann ◽

D. Reinhardt ◽

J. Hermann ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Rank Test ◽

High Dose ◽

Free Survival ◽

Log Rank Test ◽

Risk Patients ◽

Standard Risk ◽

Acute Myeloid

PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P = .01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P = .007; and 44% v 31%, P = .01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.

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The Prognostic Value and Function of HOXB5 in Acute Myeloid Leukemia

Frontiers in Genetics ◽

10.3389/fgene.2021.678368 ◽

2021 ◽

Vol 12 ◽

Author(s):

Miao Chen ◽

Yi Qu ◽

Pengjie Yue ◽

Xiaojing Yan

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Cell Differentiation ◽

Myeloid Leukemia ◽

Hox Genes ◽

Interaction Analysis ◽

Quantitative Polymerase Chain Reaction ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Acute Myeloid

BackgroundCurrently, cytogenetic and genetic markers are the most important for risk stratification and treatment of patients with acute myeloid leukemia (AML). Despite the identification of many prognostic factors, relatively few have made their way into clinical practice. Therefore, the identification of new AML biomarkers is useful in the prognosis and monitoring of AML and contributes to a better understanding of the molecular basis of the disease. Homeobox (HOX) genes are transcription factors that lead to cell differentiation blockade and malignant self-renewal. However, the roles of HOX genes in AML are still not fully understood and need further exploration, which may provide new strategies for the prognosis and monitoring of AML.MethodsWe analyzed the RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA), VIZOME, GSE13159, and GSE9476 cohorts. Analyses were performed with GraphPad 7, the R language, and several online databases. We applied quantitative polymerase chain reaction, Western Blotting, CCK8 cell proliferation assays, and flow cytometry to verify the conclusions of the bioinformatics analysis.ResultsWe identified HOXB5 as the only gene among the HOX family that was not only elevated in AML but also a significant prognostic marker in AML patients. HOXB5 was highly expressed in AML patients with NPM1, FLT3, or DNMT3A mutations and was expressed at the highest level in patients with NPM1-FLT3-DNMT3A triple-mutant AML. Gene Ontology analysis and gene set enrichment analysis revealed that HOXB5 showed a negative correlation with the myeloid cell differentiation signature and that the tumor necrosis factor/nuclear factor κB signaling pathway was involved in the molecular mechanism. Moreover, we performed in silico protein–protein interaction analysis and 450K TCGA DNA methylation data analysis and found that HOXB5 interacted with two HOX genes (HOXA7 and HOXB4) that were commonly regulated by DNA methylation levels.ConclusionHOXB5 is associated with the malignant development of AML and may be a treatment target and biomarker for AML prognosis prediction.

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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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Decitabine induces very early in vivo DNA methylation changes in blasts from patients with acute myeloid leukemia

Leukemia Research ◽

10.1016/j.leukres.2012.10.015 ◽

2013 ◽

Vol 37 (2) ◽

pp. 190-196 ◽

Cited By ~ 20

Author(s):

Rainer Claus ◽

Dietmar Pfeifer ◽

Maika Almstedt ◽

Manuela Zucknick ◽

Björn Hackanson ◽

...

Keyword(s):

Dna Methylation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Acute Myeloid

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Long-Term Prognosis of Acute Myeloid Leukemia According to the New Genetic Risk Classification of the European LeukemiaNet Recommendations: Evaluation of the Proposed Reporting System

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.8500 ◽

2011 ◽

Vol 29 (20) ◽

pp. 2758-2765 ◽

Cited By ~ 143

Author(s):

Christoph Röllig ◽

Martin Bornhäuser ◽

Christian Thiede ◽

Franziska Taube ◽

Michael Kramer ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Reporting System ◽

Young Patients ◽

Risk Classification ◽

Rank Test ◽

Kaplan Meier ◽

Heterogenous Group ◽

Long Term Prognosis ◽

Acute Myeloid

Purpose The current European LeukemiaNet (ELN) recommendations for acute myeloid leukemia (AML) propose a new risk reporting system, integrating molecular and cytogenetic factors and subdividing the large heterogenous group of intermediate-risk patients into intermediate-I (IR-I) and intermediate-II (IR-II). We assessed the prognostic value of the new risk classification in a large cohort of patients. Patients and Methods Complete data for classification were available for 1,557 of 1,862 patients treated in the AML96 trial. Patients were assigned to the proposed genetic groups from the ELN recommendations, and survival analyses were performed using the Kaplan-Meier method and log-rank test for significance testing. Results The median age of all patients was 67 years. With a median follow-up of 8.3 years, significant differences between all risk categories were observed in patients age ≤ 60 years regarding the time to relapse, relapse-free survival, and overall survival (OS). Patients in the IR-II group had a better prognosis than patients in the IR-I group. The median OS times in young patients with favorable risk (FR), IR-I, IR-II, and adverse risk (AR) were 5.3, 1.1, 1.6, and 0.5 years, respectively. Separate analyses in the age group older than 60 years revealed significant differences between FR, AR, and IR as a whole, but not between IR-I and IR-II. Conclusion In younger patients with AML, the ELN classification seems to be the best available framework for prognostic estimations to date. Caution is advised concerning its use for prospective treatment allocation before it has been prospectively validated. In elderly patients, alternative prognostic factors are desirable for further risk stratification of IR.

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