Marker In Acute Myeloid Leukemia Research Articles

Long non-coding RNA as potential diagnostic markers for acute myeloid leukemia: A systematic review and meta-analysis.

Acute myeloid leukemia (AML) is aggressive type of hematological malignancy. Its poses challenges in early diagnosis, necessitating the identification of an effective biomarker. This study aims to assess the diagnostic accuracy of long noncoding RNAs (lncRNA) in the diagnosis of AML through a meta-analysis. The study is registered on the PROSPERO website with the number 493518. A literature search was conducted in the PubMed, Embase, Hinari, and the Scopus databases to identify relevant studies. We pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the summary receiver operating characteristics (ROC) using Stata 14.1 software. Heterogeneity between studies was determined through the I2 statistic and Cochran-Q test. A random effect model was chosen due to significant heterogeneity among included studies. Meta-regression and subgroup analysis were performed to assess the potential source of heterogeneity. Furthermore, potential publication bias was estimated using Deek's funnel plot asymmetry test. A total of 14 articles covering 19 studies were included in this meta-analysis comprising 1588 AML patients and 529 healthy participants. The overall pooled sensitivity, specificity, PLR, NLR, DOR, and the area under the summary ROC curve were 0.85 (95% CI = 0.78-0.91), 0.82 (95% CI = 0.72-0.89), 4.7 (95% CI = 2.9-7.4), 0.18 (95% CI = 0.12-0.28), 26 (95% CI = 12-53), and 0.90 (95% CI = 0.87-0.93), respectively. Moreover, lncRNAs from non-bone marrow mononuclear cells (BMMC) had superior diagnostic value with pooled sensitivity, specificity, and AUC were 0.93, 0.82, and 0.95, respectively. This meta-analysis demonstrated that circulating lncRNAs can serve as potential diagnostic markers for AML. High accuracy of diagnosis was observed in non-BMMC lncRNAs, given cutoff value, and the GADPH internal reference gene used. However, further studies with large sample size are required to confirm our results.

N6-methyladenosine-modified SENP1, identified by IGF2BP3, is a novel molecular marker in acute myeloid leukemia and aggravates progression by activating AKT signal via de-SUMOylating HDAC2

BackgroundElevated evidence suggests that the SENPs family plays an important role in tumor progression. However, the role of SENPs in AML remains unclear.MethodsWe evaluated the expression pattern of SENP1 based on RNA sequencing data obtained from OHSU, TCGA, TARGET, and MILE datasets. Clinical samples were used to verify the expression of SENP1 in the AML cells. Lentiviral vectors shRNA and sgRNA were used to intervene in SENP1 expression in AML cells, and the effects of SENP1 on AML proliferation and anti-apoptosis were detected using in vitro and in vivo models. Chip-qPCR, MERIP-qPCR, CO-IP, RNA pulldown, and dual-luciferase reporter gene assays were used to explore the regulatory mechanisms of SNEP1 in AML.ResultsSENP1 was significantly upregulated in high-risk AML patients and closely related to poor prognosis. The AKT/mTOR signaling pathway is a key downstream pathway that mediates SENP1's regulation of AML proliferation and anti-apoptosis. Mechanistically, the CO-IP assay revealed binding between SENP1 and HDAC2. SUMO and Chip-qPCR assays suggested that SENP1 can desumoylate HDAC2, which enhances EGFR transcription and activates the AKT pathway. In addition, we found that IGF2BP3 expression was upregulated in high-risk AML patients and was positively correlated with SENP1 expression. MERIP-qPCR and RIP-qPCR showed that IGF2BP3 binds SENP1 3-UTR in an m6A manner, enhances SENP1 expression, and promotes AKT pathway conduction.ConclusionsOur findings reveal a distinct mechanism of SENP1-mediated HDAC2-AKT activation and establish the critical role of the IGF2BP3/SENP1signaling axis in AML development.

Assessment of Measurable Residual Disease on Day 28 of First Induction Chemotherapy in Acute Myeloid Leukaemia Patients

Background: Measurable residual disease (MRD) is an independent, strong, prognostic marker in acute myeloid leukaemia (AML) that is important for risk stratification and treatment planning. This study assessed the MRD on day-28 after first induction chemotherapy in AML patients. Objective: To assess measurable residual disease status on day 28 after the first induction chemotherapy in newly diagnosed acute myeloid leukaemia patients. Methodology: This cross-sectional study was conducted at the Department of Haematology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from April 2021 to March 2022 among a total of 25 newly diagnosed AML patients who were admitted and received induction chemotherapy with DA (7+3). On Day-28, bone marrow aspiration was done with standard procedure and first pull of 2ml bone marrow sample was sent to a laboratory for MRD evaluation by multiparameter flow cytometry. MRD was considered positive when value was ?0.1%. Results: On day 28 of post induction chemotherapy most of the patients (92%) achieved morphological remission and among them more than half (52.2%) were MRD positive. The presence of CD14 myeloid marker and baseline higher serum uric acid level was significant in MRD positive patients and cytarabine dose 150 mg/m2 was found significant in MRD negative patients. Conclusion: More than half of the Acute Myeloid Leukaemia patients, treated with standard induction chemotherapy and achieved morphological remission on day 28 of chemotherapy, had positive measurable residual disease assessed by multiparameter flow cytometry. Positive MRD indicates relatively poorer prognosis and may necessitate more cycles of induction followed by more intensive consolidation which may include haematopoietic stem cell transplantation.

CD 11b and CD56 As Prognostic Markers in Acute Myeloid Leukemia

CD 11b and CD56 As Prognostic Markers in Acute Myeloid Leukemia

Real-World Data for FLT3-Mutated Acute Myeloid Leukemia Patients Treated in Resource-Constrained Settings

Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a well-established prognostic marker in acute myeloid leukemia (AML), whereas the impact of mutations in the Tirosine-Kinase Domain (TKD) is controversial. The association of TK inhibitors (TKIs) with intensive chemotherapy improved the overall survival (OS) of FLT3-mutated AML patients in randomized clinical trials and is recommended by the European LeukemiaNet panel of experts. Nevertheless, TKIs are not available for most patients treated in Low- and Middle-Income Countries (LMIC) and there is a scarcity of data concerning the outcome of treatment in these resource-constrained settings nowadays. Methods: This is a real-world study encompassing newly diagnosed adults with FLT3-mutated AML intensively treated at public hospitals in Brazil between January 2015 and December 2020, who were registered in the International Consortium on Acute Leukemias (ICAL) ICAML2015 Study. No patient received TKIs as part of the treatment. FLT3 mutation was tested in diagnostic samples by fragment analysis method. We used the Adapted Genetic Risk (AGR) score reported by Silveira et al. (2020), which is an adaptation of the European Leukemia Net (ELN) 2017 classification. The primary endpoints were event-free survival (EFS) and OS, calculated by Kaplan-Meier method. Relapse rate was calculated through competing risk analysis. Results: Overall, 350 pts (median age: 51y; 52.8% females) were included. FLT3-ITD and -TKD mutations were detected in 17.5% and 7.2% of the patients, respectively. Ninety patients (35.1%) were classified in the favorable risk group, 110 (42.9%) in the intermediate, and 56 (21.9%) in the adverse risk group, according to the AGR. The most frequent co-mutation was in the NPM1 gene. The remaining features are summarized in Table 1. Seventy-eight patients underwent allogeneic stem-cell transplantation (HSCT) in first complete remission (22.2%), of whom 27 had FLT3-ITD (i.e. 43.9% of patients harboring FLT3-ITD underwent HSCT). With a median follow-up period of 3.5 years, the median 4-year OS rate was 24.2% (95% CI 19.8-30.1), and the 4-y EFS 22.9% (95% CI 18.6-28.2). When only patients with FLT3-ITD mutations were analyzed, the 4-y OS rate was 14.4% which was inferior to that of patients with wild-type FLT3 (27.5%; p=0.057) (Figure 1). The cumulative incidence of relapse at four years was 39.4% for patients with FLT3-ITD and 43.9% for those with wildtype FLT3 (p=0.5), while the non-relapse mortality (NRM) at four years was 28.1% and 32.4%, respectively. The four-year OS rate for patients with FLT3-ITD mutations who underwent HSCT was 49.1% (95% CI 38.9-62.1). Patients with FLT3-ITD were further subdivided according to the allelic ratio (AR) in those with low (<0.5) and high (³ 0.5), and no significant difference in OS was detected between the two groups. Of note that patients harboring FLT3-TKD mutations showed a better overall survival rate compared to those with wild-type FLT3 (HR 0.49, 95% CI 0.26-0.93, p=0.029), but this result needs to be interpreted cautiously due the small size of the cohort. Conclusion: our results show that the frequency of FLT3-ITD mutations and their association with worse prognosis was similar to those described in high-income countries previously to the introduction of TKI as the standard of care. Therefore, allogeneic HSCT remains a valid consolidation strategy for FLT3-mutated patients. However, less than half of the patients for whom HSCT was indicated were actually transplanted. Additionally, the allelic ratio of FLT3-ITD should no longer be considered a prognostic marker for intensively treated patients not receiving FLT3 inhibitors.

Serum circRNA_100199 is a Prognostic Biomarker in Acute Myeloid Leukemia.

An aberrant level of serum microRNA expression has been demonstrated to be a prognostic marker for acute myeloid leukemia (AML). The therapeutic relevance of serum circRNA 100199 remained unknown, however. This research aimed to investigate the probable prognostic significance of serum circRNA_100199 for AML. This study included a total of 200 participants consisting of 114 AML-diagnosed patients and 86 healthy people. Blood samples were taken, and the level of circRNA_100199 in the serum was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) to explore its potential clinical significance. Our study demonstrated that circRNA_100199 expression in the serum was substantially higher in AML subjects than in healthy persons. This increase in serum circRNA_100199 levels was particularly noticeable in M4/M5 subtype AML patients, and those with poor cytogenetic risk or higher white blood cell counts. Using receiver operating characteristic (ROC) analysis, AML cases were effectively differentiated from healthy persons based on the level of serum circRNA_100199. Furthermore, it was found that high serum circRNA_100199 expression was strongly linked with shorter survival times and more severe clinical features. Our study also confirmed that high serum circRNA_100199 expression was an independent predictor of relapse-free survival (RFS) and overall survival (OS) in AML patients. Interestingly, the serum expression level of circRNA_100199 was significantly reduced following treatment, and its levels were substantially lower in AML patients who achieved complete remission (CR) than those who did not. Overall, these findings suggest that serum circRNA_100199 has the potential to be a favorable prognostic biomarker for AML.

Nutritional and prognostic value of bioelectrical phase angle as a potentially modifiable marker in acute myeloid leukemia.

Phase angle (PhA), as measured by bioelectrical impedance analysis, is an important parameter in nutritional assessment and is highly predictive of clinical outcomes in various diseases; however, there is little research on its use in acute myeloid leukemia (AML). Therefore, the present study was conducted to determine the association between PhA and malnutrition and to clarify the prognostic significance of PhA for progression-free survival (PFS) and overall survival (OS) in adult patients with AML (excluding acute promyelocytic leukemia) who were undergoing chemotherapy. A total of 70 patients with newly diagnosed AML were enrolled. After chemotherapy, the nutritional risk for patients with a reduced baseline PhA increased significantly. Disease progression occurred in 28 patients, of which 23 died, with a median follow-up of 9.3 months. A reduced baseline PhA was associated with poor PFS (7.1 months vs. 11.6 months; P=0.001) and OS (8.2 months vs. 12.1 months; P=0.011). A multivariate analysis revealed that a reduced PhA was an independent risk factor for disease progression (hazard ratio, 3.13; 95% CI, 1.21-8.11; P=0.019). Overall, these results suggested that PhA is an effective and sensitive indicator that may provide important nutritional and prognostic information in patients with AML.

Downregulation of IRAIN long non-coding RNA predicts unfavourable clinical outcome in acute myeloid leukaemia patients

Background Although it has been shown that the long non-coding RNA (lncRNA) insulin-like growth factor type 1 receptor (IGF1R) antisense imprinted non-protein coding RNA (IRAIN) is downregulated in leukaemia cell lines, its usefulness as a prognostic marker in acute myeloid leukaemia (AML) has not yet been thoroughly investigated. Here, we sought to determine whether the expression of IRAIN is associated with clinical outcome of AML patients. Subjects & Methods Using quantitative real-time polymerase chain reaction (qRT-PCR), IRAIN expression levels were assessed in peripheral blood leukocyte samples from 150 patients with AML and 50 healthy controls. Analysis was done on the relationship between IRAIN expression and clinical outcomes in AML patients. Results When compared to healthy controls, IRAIN expression was markedly reduced in AML patients (P = 0.019). IRAIN expression could distinguish French-American-British (FAB) subtypes of AML (P = 0.024). Low IRAIN expression status was associated with shorter event-free survival (EFS) in the non-t(15;17) cytogenetically abnormal AML subset (P = 0.004). IRAIN downregulation was identified as an independent adverse prognostic marker for complete remission (CR) not only in the in the non-t(15;17) cytogenetically abnormal AML subset (P = 0.006) but also in the AML-M4/M5 subgroup (P = 0.033). Conclusion Aberrantly low IRAIN expression is closely associated with lower CR rates in AML patients, particularly in non-t(15;17) cytogenetically abnormal AML and M4/M5 AML, suggesting that the determination of IRAIN expression level at diagnosis provides valuable prognostic information, serves as a promising biomarker for evaluating treatment response, and helps predicting clinical outcome of AML patients.

FLT3-ITD Measurable Residual Disease Monitoring in Acute Myeloid Leukemia Using Next-Generation Sequencing.

The in-frame internal tandem duplication (ITD) of the FMS-like tyrosine kinase 3 (FLT3) gene is an important negative prognostic marker in acute myeloid leukemia (AML). FLT3-ITD monitoring is essential for patients at relapse or those receiving FLT3-targeted therapies. Fragment analysis (FA) is commonly used to detect and quantify FLT3-ITDs; however, detecting low-burden FLT3-ITDs after a treatment is challenging. We, therefore, developed a customized, next-generation sequencing (NGS)-based FLT3-ITD assay that includes a new ITD-tracing algorithm, "SEED", optimized for measurable residual disease (MRD) monitoring. NGS-SEED showed an enhanced sensitivity (0.001%) and has a superior performance over conventional fragment analysis. We further investigated the prognostic impact of MRD analyzed by NGS-SEED in AML patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Our assay showed that the MRD assessed before and after HSCT were significantly associated with a risk of relapse and a poor overall survival, respectively, in a time-dependent analysis. Thus, this report highlighted the prognostic value of serial MRD monitoring using a sensitive method in a clinical setting of AML patients with FLT3-ITD.

Machine Learning Allows the Identification of New Co-Mutational Patterns with Prognostic Implications in NPM1 Mutated AML - Results of the European Harmony Alliance

Background: Mutations of NPM1 are generally considered as a favorable prognostic marker in acute myeloid leukemia (AML), although patients present with distinct co-mutations that might influence outcomes. The recently updated European LeukemiaNet classification (ELN2022) does now group NPM1mut AML patients with FLT3-ITD (regardless of the allelic ratio) as intermediate prognosis, while NPM1mut without FLT3-ITD is part of the favorable group. However, the mutational landscape of NPM1mut AML is more complex and analysis of a large cohort of patients might allow further dissection to identify less frequent co-mutational patterns of prognostic and predictive importance. Aims: To identify clinically significant co-mutational patterns in NPM1mut AML to further refine risk stratification models for this subset of patients. Methods: From the HARMONY Alliance database, a total of 1093 intensively treated NPM1mut patients were selected. Patients treated with targeted therapies (e.g. FLT3 or IDH1/2 inhibitors) were not included and NPM1 MRD information was not available at this stage of the analysis. A machine learning algorithm was developed in order to identify combinations of up to 4 co-mutated genes with potential impact on overall survival (OS). A heuristic search algorithm was implemented and bootstrap sampling was applied to estimate the impact of all possible gene combinations on OS. In addition, a global dashboard was developed where it was possible to compare mutational combinations with Kaplan Meier and Cox regression models. Finally, clinically significant co-mutational patterns were summarized in a novel risk stratification model for NPM1mut AML, which was validated using a publicly available external patient cohort (Awada et al, Blood, 2021). Results: The study population of 1093 NPM1mut AML patients included 57% females and median age was 53 years. Regarding ELN2022 classification, 57% of patients were classified into the favorable, 42% into intermediate and only 1% into adverse risk groups. The most frequent co-mutations were DNMT3A (54%) and FLT3-ITD (42%), followed by NRAS, FLT3-TKD and TET2 (20% each). Mutations on IDH1 (13%) and IDH2 (15%) showed a similar behavior for all the analyses performed, so for simplification purposes we will refer to IDHmut when any of them was mutated and to IDHwt when both were wildtype. The triple combination of NPM1mut + FLT3-ITD + DNMT3Amut identified a subgroup of patients with adverse prognosis (2-year OS of 33%), similar to patients with TP53mut. Of note, not all FLT3-ITD patients carried an intermediate or adverse prognosis, as we were able to identify a subgroup (FLT3-ITD + IDHmut + DNMT3Awt) with excellent prognosis (2-year OS of 80%), which represented 4% of NPM1mut AML. However, in the absence of FLT3-ITD and the presence of DNMT3Amut, the addition of IDHmut decreased OS towards the intermediate risk (2-year OS 59%). Notably, not all DNMT3Amut patients carried an intermediate or adverse prognosis. In the absence of FLT3-ITD and with IDHwt, mutations on either NRAS, KRAS, PTPN11 or RAD21 revealed a subgroup with favorable prognosis even when DNMT3A was mutated (2-year OS 80%) and this group represented 11% of NPM1mut AML. This information is summarized in a 4-category risk stratification model (figure 1). The revised NPM1mut favorable group presented with a 3-year OS of 78%, which was 63%, 48% and 29% for intermediate-1, intermediate-2 and adverse risk groups respectively (p<0.001). Regarding 3-year relapse free survival (RFS), it was 71%, 59%, 39% and 26% accordingly (p<0.001). In the validation cohort, 3-year OS of was 73% for NPM1mut favorable group, being 59%, 40% and 22% for intermediate-1, intermediate-2 and adverse groups respectively (p<0.001). Multivariate OS analysis in NPM1mut AML identified the following independent prognostic factors: revised NPM1mut model (taking favorable group as reference, HR 1.77 for intermediate-1, HR 2.92 for intermediate-2 and HR 5.13 for adverse group, p<0.001); secondary or therapy-related AML (HR 1.93, p<0.001), age >60 years (HR 1.84, p<0.001), WBC at diagnosis >100x103/uL (HR 1.59, p<0.001), and male gender (HR 1.21, p=0.04). Conclusion/summary: Analysis of large NPM1mut AML cohorts allows the identification of clinically significant co-mutational patterns. We propose a new genetic stratification model for NPM1mut AML that identifies 4 groups with different OS and RFS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

18. Cell-free DNA 5-hydroxymethylcytosine is an emerging marker of acute myeloid leukemia

18. Cell-free DNA 5-hydroxymethylcytosine is an emerging marker of acute myeloid leukemia

Frugal alignment-free identification of FLT3-internal tandem duplications with FiLT3r

BackgroundInternal tandem duplications in the FLT3 gene, termed FLT3-ITDs, are useful molecular markers in acute myeloid leukemia (AML) for patient risk stratification and follow-up. FLT3-ITDs are increasingly screened through high-throughput sequencing (HTS) raising the need for robust and efficient algorithms. We developed a new algorithm, which performs no alignment and uses little resources, to identify and quantify FLT3-ITDs in HTS data.ResultsOur algorithm (FiLT3r) focuses on the k-mers from reads covering FLT3 exons 14 and 15. We show that those k-mers bring enough information to accurately detect, determine the length and quantify FLT3-ITD duplications. We compare the performances of FiLT3r to state-of-the-art alternatives and to fragment analysis, the gold standard method, on a cohort of 185 AML patients sequenced with capture-based HTS. On this dataset FiLT3r is more precise (no false positive nor false negative) than the other software evaluated. We also assess the software on public RNA-Seq data, which confirms the previous results and shows that FiLT3r requires little resources compared to other software.ConclusionFiLT3r is a free software available at https://gitlab.univ-lille.fr/filt3r/filt3r. The repository also contains a Snakefile to reproduce our experiments. We show that FiLT3r detects FLT3-ITDs better than other software while using less memory and time.

Cell-free DNA 5-hydroxymethylcytosine is an emerging marker of acute myeloid leukemia

Aberrant changes in 5-hydroxymethylcytosine (5hmC) are a unique epigenetic feature in many cancers including acute myeloid leukemia (AML). However, genome-wide analysis of 5hmC in plasma cell-free DNA (cfDNA) remains unexploited in AML patients. We used a highly sensitive and robust nano-5hmC-Seal technology and profiled genome-wide 5hmC distribution in 239 plasma cfDNA samples from 103 AML patients and 81 non-cancer controls. We developed a 5hmC diagnostic model that precisely differentiates AML patients from controls with high sensitivity and specificity. We also developed a 5hmC prognostic model that accurately predicts prognosis in AML patients. High weighted prognostic scores (wp-scores) in AML patients were significantly associated with adverse overall survival (OS) in both training (P = 3.31e−05) and validation (P = 0.000464) sets. The wp-score was also significantly associated with genetic risk stratification and displayed dynamic changes with varied disease burden. Moreover, we found that high wp-scores in a single gene, BMS1 and GEMIN5 predicted OS in AML patients in both the training set (P = 0.023 and 0.031, respectively) and validation set (P = 9.66e−05 and 0.011, respectively). Lastly, our study demonstrated the genome-wide landscape of DNA hydroxymethylation in AML and revealed critical genes and pathways related to AML diagnosis and prognosis. Our data reveal plasma cfDNA 5hmC signatures as sensitive and accurate markers for AML diagnosis and prognosis. Plasma cfDNA 5hmC analysis will be an effective and minimally invasive tool for AML management.

Screening diagnostic markers for acute myeloid leukemia based on bioinformatics analysis.

BackgroundAn in-depth understanding of the key molecules and associated mechanisms involved in acute myeloid leukemia (AML) carcinogenesis, proliferation, and relapse is critical. This provides a basis for disease screening, early diagnosis, and development of effective treatment strategies and prognosis.MethodsWe downloaded AML transcription data sets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially expressed genes (DEGs) were screened by R software and limma packages. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on DEGs by public databases. In the DEG set, a random forest algorithm was used to identify characteristic genes of AML. The receiver operator characteristic (ROC) curve was used to evaluate the diagnostic efficacy of selected characteristic genes, which provided clues for the discovery of early diagnostic markers. The Estimate score was calculated using the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm. Spearman’s correlation test was used to explore the correlation between characteristic genes and Estimate Score, which provided clues for clarifying the potential pathogenic mechanism of key genes.ResultsA total of 1,494 DEGs were identified from AML samples and normal samples, among which 1,181 genes were upregulated and 313 genes were downregulated in AML. There were 2 genes with a mean decrease Gini >2, namely, CDC20 and ESM1, respectively. The ROC curve showed that the area under the curve (AUC) of CDC20 was 0.966, and the 95% confidence interval (CI) was (0.939 to 0.987) (P<0.001). The AUC of ESM1 was 0.905, and 95% CI: 0.849 to 0.953 (P<0.001). Correlation analysis showed that CDC20 expression was negatively correlated with Estimate Score (R=−0.21, P=0.0036) in AML. The expression of ESM1 was negatively correlated with Estimate Score (R=−0.57, P<0.001).ConclusionsThe genes CDC20 and ESM1 were identified as AML characteristic genes by random forest algorithm. Both CDC20 and ESM1 have good diagnostic efficacy for AML. They may play a carcinogenic role by promoting tumor cell proliferation and inhibiting immune cell chemotaxis, which are potential biological markers.

Evaluation of CDCP1 (CD318) and endoglin (CD105) expression as prognostic markers in acute myeloid leukemia.

The most commonly used prognostic factors in acute myeloid leukemia (AML) are cytogenetic, molecular, and morphological markers. However, AML prognosis is still unfavorable particularly in adults. So, further reliable markers are urgently needed to improve the risk stratification and treatment decisions. CUB domain-containing protein 1 (CDCP1; CD318) and endoglin (CD105) are new markers correlated with poor prognosis in different solid tumors, but their role in AML prognosis is not fully evaluated. This work aimed to evaluate the prognostic role of CD318 and CD105 in AML and their impact on the outcomes. Sixty-five newly diagnosed AML patients were included in this study. CD318 and CD105 expression was assessed by quantitative real-time polymerase chain reaction. Patients were followed up for ∼ 2 years to evaluate the prognostic impact of gene expression on the outcomes. Patients with high CD318 and CD105 showed higher white blood cell (WBC) count, M2 subtype, poor cytogenetic risk, reduced complete remission, and a greater number of deaths compared to low CD318 and CD105. CD318 was correlated with CD105, and both were correlated with WBC count, bone marrow blasts, and peripheral blood blasts. After a follow-up period of up to 24 months, relapse-free survival for high CD318 and CD105 was significantly different (42.1% and 52.6% vs. 64.5% and 58.1% for low CD318 and CD105, respectively). Survival was worse in patients with high CD318 and CD105, as the mean survival time was 13.9 and 13.3 months compared to 24 and 22.7 months in low CD318 and CD105, respectively. CD318 and CD105 are upregulated in AML patients. Their overexpression was associated with poor response to treatment and poor outcomes. Therefore, CD318 and CD105 can be useful prognostic markers in AML.

WT1 Gene Mutations, rs16754 Variant, and WT1 Overexpression as Prognostic Factors in Acute Myeloid Leukemia Patients.

(1) Background: The aim of our study was the complex assessment of WT1 variants and their expression in relation to chromosomal changes and molecular prognostic markers in acute myeloid leukemia (AML). It is the first multidimensional study in Polish AML patients; (2) Methods: Bone marrow aspirates of 90 AML patients were used for cell cultures (banding techniques and fluorescence in situ hybridization), and to isolate DNA (WT1 genotyping, array comparative genomic hybridization), and RNA (WT1 expression). Peripheral blood samples from 100 healthy blood donors were used to analyze WT1 rs16754; (3) Results: Allele frequency and distribution of WT1 variant rs16754 (A;G) did not differ significantly among AML patients and controls. Higher expression of WT1 gene was observed in AA genotype (of rs16754) in comparison with GA or GG genotypes—10,556.7 vs. 25,836.5 copies (p = 0.01), respectively. WT1 mutations were more frequent in AML patients under 65 years of age (p < 0.0001) and affected relapse-free survival (RFS). The presence of NPM1 or CEBPA mutations decreased the risk of WT1 mutation presence, odds ratio (OR) = 0.11, 95% CI 0.02–0.46, p = 0.002 or OR = 0.05, 95% CI 0.006–0.46, p = 0.002, respectively. We observed significantly higher WT1 expression in AML CD34+ vs. CD34−, −20,985 vs. 8304 (p = 0.039), respectively. The difference in WT1 expression between patients with normal and abnormal karyotype was statistically insignificant; (4) Conclusions: WT1 gene expression and its rs16754 variant at diagnosis did not affect AML outcome. WT1 mutation may affect RFS in AML.

Serum hsa_circ_0079480 is a novel prognostic marker for acute myeloid leukemia.

BackgroundThe dysregulated expression of serum circular RNAs (circRNAs) has previously been linked to the prognosis of acute myeloid leukemia (AML) patients, but the clinical and prognostic relevance of serum hsa_circ_0079480 levels in this oncogenic setting have yet to be established. Herein, we assessed the putative prognostic relevance of circulating hsa_circ_0079480 levels in AML patient serum.MethodsSerum was prepared from blood samples collected from 236 AML patients and 160 healthy controls, with hsa_circ_0079480 levels therein being quantified by quantitative real‐time reverse transcription‐polymerase chain reaction (qRT‐PCR) after which the clinical value of these levels was assessed.ResultsAcute myeloid leukemia patients were found to exhibit significant hsa_circ_0079480 upregulation in their serum as compared to serum from healthy controls, with such upregulation being most profound in individuals with M4/M5 type disease and to be more common in patients with poor cytogenic risk or high white blood cell counts. Receiver operating characteristic (ROC) curves demonstrated that serum hsa_circ_0079480 levels were able to effectively differentiate between patients with AML and healthy controls. Moreover, the upregulation of serum hsa_circ_0079480 was found to be closely related to clinicopathological findings and to be an independent predictor of reduced overall and relapse‐free survival among individuals diagnosed with AML. Furthermore, serum hsa_circ_0079480 levels were markedly decreased after treatment in this patient population, with these levels being lower in patients that achieved complete remission as compared to those patients that did not.ConclusionLevels of hsa_circ_0079480 in patient serum may offer value as a prognostic biomarker in AML.

Pathogenetic Significance of YBX1 Expression in Acute Myeloid Leukemia Relapse

BackgroundGenomic abnormalities were established as prognostic and diagnostic markers for acute myeloid leukemia (AML) tumorgenesis and YBX1 gene has important roles in different cancer types. MethodsA total of 109 adult and pediatric patients with De novo AML, were enrolled in this study. Besides the routine lab work; bone marrow YBX1 expression levels were measured using qRT-PCR, and then its possible connections to AML pathogenesis pathway were investigated by STRING tool. ResultsResults demonstrated upregulation of YBX1 expression level in AML patients that was associated with the presence of adverse genomics abnormalities. In adult patients, the level of YBX1 expression was significantly high in relapsed and resistant groups, while in pediatric patients, the level of YBX1 expression showed an inverse pattern as it was highly expressed in complete remission group. STRING analysis highlighted that YBX1 interacts with important factors in the AML signaling pathway. Kaplan-Meier analysis indicated that adult patients with highly expressed YBX1 significantly endured shorter disease-free survival (DFS) compared to low YBX1 expressers and there was no impact of YBX1 on adult patients overall survival (OS). While pediatric patients with upregulated YBX1 showed good OS over downregulated patients. ConclusionIn conclusion, YBX1 may have a crucial role in AML relapse pathogenesis. Also, it could serve as a prognostic factor for AML disease outcomes.

FGF10/FGF17 as prognostic and drug response markers in acute myeloid leukemia

BackgroundFibroblast growth factors (FGFs) play important roles in solid tumor progression. Little is known about the function and the prognostic value of distinct FGFs in acute myeloid leukemia (AML). MethodsWe used dataset from Beat AML to screen the FGFs family in AML by log-rank test. Subsequently, we identified the biological functions and the crucial signaling pathways associated with these screened FGFs using gene set enrichment analysis (GSEA). In addition, IC50 from 122 small-molecule inhibitors was used to explore the relationship between these signaling pathways and targets of sensitive inhibitors. ResultsAmong the FGFs family, over expressions of FGF10/FGF17 were found to be significantly associated with poor prognosis. FGF10 over expression was related to FLT3 and NPM1 mutations, and FGF17 over expression was linked to MUC12 and ZRSR2 mutations. Some cancer-related pathways such as PI3K-Akt, MAPK were significantly enriched by GSEA, and these pathways were concordant with sensitive inhibitors targeted pathways. ConclusionOur results indicated that FGF10 and FGF17 could be prognostic biomarkers for survivals of AML patients, and potential therapeutic targets for small-molecule inhibitors.

The prospective prognostic value of the immune checkpoint BTLA expression in adult acute myeloid leukemia patients

BackgroundOne of the crucial functions of the immune system is to prevent tumorigenesis, yet cancer occurs when malignant cells manage to evade immune surveillance via multiple strategies. Accordingly, this study aimed at assessing the potential significance of the novel immune checkpoint B and T lymphocyte attenuator (BTLA) as a prognostic marker in acute myeloid leukemia (AML), in addition to how it relates to response to treatment and patients’ survival. Thus, mRNA expression of BTLA was investigated on peripheral blood in 60 AML patients and 15 healthy controls.ResultsBTLA expression was found to be significantly elevated (p = 0.024) in the tested AML cases in comparison with healthy controls. Moreover, BTLA was over-expressed in the CD13, CD33, and HLA-DR positive cases as compared to their negative counterparts (p = 0.003; p < 0.001, and p = 0.001, respectively), and cases showing BTLA over-expression had significantly poorer overall survival times (p = 0.001) as confirmed by Kaplan–Meier survival analysis.ConclusionThese observations suggest that BTLA over-expression may be associated with reduced immunity against tumors and could be recommended as a promising biomarker for unfavorable prognosis in AML.