Prognosis In Acute Myeloid Leukemia Research Articles

MiR-26b-5p Affects the Progression of Acute Myeloid Leukemia by Regulating the USP48-Mediated Wnt/β-Catenin Pathway.

Acute myeloid leukemia (AML) is a highly heterogeneous disease. Exploring the pathogenesis of AML is still an important topic in the treatment of AML. The expression levels of miR-26b-5p and USP48 were measured by qRT-PCR. The expression levels of related proteins were detected by Western blot. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. Coimmunoprecipitation was used to examine the interaction between USP48 and Wnt5a. Bioinformatics analysis showed that high levels of miR-26b-5p and low levels of USP48 were associated with poor prognosis in AML. miR-26b-5p can negatively regulate the expression of USP48. Downregulation of miR-26b-5p inhibited EMT, cell viability and proliferation of AML cells and accelerated apoptosis. Furthermore, the influence of miR-26b-5p inhibition and USP48 knockdown on AML progression could be reversed by a Wnt/β-catenin signaling pathway inhibitor. This study revealed that miR-26b-5p regulates AML progression, possibly by targeting the USP48-mediated Wnt/β-catenin molecular axis to affect AML cell biological behavior.

Clinical profile of FTL3-ITD mutation in West Algerian population with acute myeloid leukemia.

Acute myeloid leukemia(AML) is a cancer of the myeloid line of blood cells, characterized by the abnormal and rapid growth of cells. The mutation of the Fms-like tyrosine kinase 3 ligand gene (FLT3-ITD) represents an important factor in the prognosis of AML. The objective of this study was to determine for the first time the prevalence of FLT3-ITD mutation in west Algerian AML patients. A total of 160 AML patients were genotyped for FLT3-ITD mutation by using polymerase chain reaction. FLT3-ITD mutation was detected in 13% of patients. Mutation rates show no significant difference in the distribution of sex and age. A positive association was found between this mutation and a higher leukocyte and blast cells counts. We also found that the M3 and M5 subtype were the commonest in the FLT3 mutated group. This preliminary study provides first-time prevalence estimates for FLT3-ITD mutation in acute myeloid leukemia patients from the West region of Algeria.

Prognostic significance of ASXL1 mutations in acute myeloid leukemia: A systematic review and meta-analysis.

Although genetic mutations in additional sex-combs-like 1 (ASXL1) are prevalent in acute myeloid leukemia (AML), their exact impact on the AML prognosis remains uncertain. Hence, the present article was carried out to explore the prognostic importance of ASXL1 mutations in AML. We thoroughly searched electronic scientific databases to find eligible papers. Twenty-seven studies with an overall number of 8,953 participants were selected for the current systematic review. The hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were extracted from all studies with multivariate or univariate analysis. Pooled HRs and p-values were also calculated as a part of our work. The pooled HR for OS in multivariable analysis indicated that ASXL1 significantly diminished survival in AML patients (pooled HR: 1.67; 95% CI: 1.342-2.091). ASXL1 mutations may confer a poor prognosis in AML. Hence, they may be regarded as potential prognostic factors. However, more detailed studies with different ASXL1 mutations are suggested to shed light on this issue.

Characterization of ligand-receptor pair in acute myeloid leukemia: a scoring model for prognosis, therapeutic response, and T cell dysfunction.

The significance of ligand-receptor (LR) pair interactions in the progression of acute myeloid leukemia (AML) has been the focus of numerous studies. However, the relationship between LR pairs and the prognosis of AML, as well as their impact on treatment outcomes, is not fully elucidated. Leveraging data from the TCGA-LAML cohort, we mapped out the LR pair interactions and distinguished specific molecular subtypes, with each displaying distinct biological characteristics. These subtypes exhibited varying mutation landscapes, pathway characteristics, and immune infiltration levels. Further insight into the immune microenvironment among these subtypes revealed disparities in immune cell abundance. Notably, one subtype showed a higher prevalence of CD8 T cells and plasma cells, suggesting increased adaptive immune activities. Leveraging a multivariate Lasso regression, we formulated an LR pair-based scoring model, termed "LR.score," to classify patients based on prognostic risk. Our findings underscored the association between elevated LR scores and T-cell dysfunction in AML. This connection highlights the LR score's potential as both a prognostic marker and a guide for personalized therapeutic interventions. Moreover, our LR.score revealed substantial survival prediction capacities in an independent AML cohort. We highlighted CLEC11A, ICAM4, ITGA4, and AVP as notably AML-specific. qRT-PCR analysis on AML versus normal bone marrow samples confirmed the significant downregulation of CLEC11A, ITGA4, ICAM4, and AVP in AML, suggesting their inverse biomarker potential in AML. In summary, this study illuminates the significance of the LR pair network in predicting AML prognosis, offering avenues for more precise treatment strategies tailored to individual patient profiles.

Prognostic importance of NUP98-rearrangements in acute myeloid leukemia: A systematic review and meta-analysis.

NUP98 gene fusions in acute myeloid leukemia (AML) have recently attracted much interest. Despite substantial research illuminating the roles of NUP98 fusions in the course of AML, their impacts on the outcome of patients with AML should be explored in more detail. As a result, this meta-analysis was designed to provide further light on the prognostic implications of NUP98 fusions in AML. We completed an extensive search in PubMed, Scopus, and Web of Science to identify papers evaluating the prognostic effects of NUP98 rearrangements in patients with AML until August 22, 2022. In total, 15 publications with 6142 participants fulfilled the requirements for the current meta-analysis. All the qualified studies were examined for information regarding HRs and 95% confidence interval (95%CI) for overall survival (OS) and event-free survival (EFS). In addition, we utilized Comprehensive Meta-analysis software version 2 (CMA2) for calculating pooled HRs and 95% CI. Our Results : analyses for NUP98-NSD1 indicated that this fusion could significantly impact the outcome of patients with AML (pooled HR: 2.84; 95% CI: 2.49-3.24, P=0.000). Additionally, we observed a strong correlation between NUP98-KDM5A rearrangement and poor prognosis in AML (pooled HR: 2.65; 95% CI: 2.5-2.81; P=0.000). A subgroup analysis also showed that the NUP98-NSD1 and FLT3-ITD together confer a poor prognostic effect (pooled HR: 2.60, 95% CI: 1.61-4.18; P=0.000). NUP98 fusions could significantly impact the outcome of patients with AML. The use of these fusions as prognostic indicators in AML seems rational.

Integrated genetic, epigenetic, and immune landscape of TP53 mutant AML and higher risk MDS treated with azacitidine.

TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53-mutated AML/HR-MDS is not well defined. To define the genetic, epigenetic, and immunologic landscape of TP53-mutant and TP53 wild-type AML and HR-MDS patients. Post hoc analysis of TP53-mutant and TP53 wild-type patients treated on the randomized FUSION trial with azacitidine ± the anti-PD-L1 antibody durvalumab. We performed extensive molecular, epigenetic, and immunologic assays on a well-annotated clinical trial dataset of 61 patients with TP53-mutated disease (37 AML, 24 MDS) and 144 TP53 wild-type (89 AML, 55 MDS) patients, all of whom received azacitidine-based therapy. A 38 gene-targeted myeloid mutation analysis from screening bone marrow (BM) was performed. DNA methylation arrays, immunophenotyping and immune checkpoint expression by flow cytometry, and gene expression profiles by bulk RNA sequencing were assessed at baseline and serially during the trial. Global DNA methylation from peripheral blood was independent of TP53 mutation and allelic status. AZA therapy led to a statistically significant decrease in global DNA methylation scores independent of TP53 mutation status. In BM from TP53-mutant patients, we found both a higher T-cell population and upregulation of inhibitory immune checkpoint proteins such as PD-L1 compared to TP53 wild-type. RNA sequencing analyses revealed higher expression of the myeloid immune checkpoint gene LILRB3 in TP53-mutant samples suggesting a novel therapeutic target. This integrated analysis of the genetic, epigenetic, and immunophenotypic landscape of TP53 mutant AML/HR-MDS suggests that differences in the immune landscape resulting in an immunosuppressive microenvironment rather than epigenetic differences contribute to the poor prognosis of TP53-mutant AML/HR-MDS with mono- or multihit TP53 mutation status. FUSION trial (NCT02775903).

The roles of phosphorylation of signaling proteins in the prognosis of acute myeloid leukemia.

Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients. We investigated the presence of phosphorylated Rb (P-Rb), Akt (P-Akt) and Erk (P-Erk) proteins by Western blot technique using phospho-specific antibodies in bone marrow or peripheral blood samples of 69 AML patients, 36 patients with myelodysplastic syndrome (MDS) and 10 healthy volunteers. Expression level of PTEN (Phosphatase and tensin homolog) and PHLPP (PH domain and leucine-rich repeat Protein Phosphatase) phosphatases, the negative regulators of Akt kinase pathway were also examined. We tested the effect of these proteins on survival and on the correlation with known prognostic features in AML. We found 46.3% of AML patients had detectable P-Rb, 34.7% had P-Akt and 28.9% had P-Erk protein. 66.1% of patients expressing PTEN, 38.9% PHLPP, 37.2% both PTEN and PHLPP and 32.2% neither PTEN nor PHLPP phosphatases. Compared to nucleophosmin mutation (NPMc) negative samples P-Erk was significantly less in nucleophosmin mutated patients, P-Rb was significantly less in patients' group with more than 30G/L peripheral leukocyte count by diagnosis. PHLPP was significantly present in FAB type M5. The expression of P-Rb represented significant better overall survival (OS), while P-Akt represented significantly worse event-free survival (EFS) in unfavorable cytogenetics patients. The presence of both PHLPP and PTEN phosphatases contributes to better OS and EFS, although the differences were not statistically significant. We confirmed significant positive correlation between P-Akt and PHLPP. Assessing the phosphorylation of Rb, Akt and Erk may define a subgroup of AML patients who would benefit especially from new targeted treatment options complemented the standard chemotherapy, and it may contribute to monitoring remission, relapse or progression of AML.

MiR-133a and miR-135a Regulate All-Trans Retinoic Acid-Mediated Differentiation in Pediatric Acute Myeloid Leukemia by Inhibiting CDX2 Translation and Serve as Prognostic Biomarkers.

Background: Acute myeloid leukemia (AML) is a type of blood cancer characterized by excessive growth of immature myeloid cells. Unfortunately, the prognosis of pediatric AML remains unfavorable. It is imperative to further our understanding of the mechanisms underlying leukemogenesis and explore innovative therapeutic approaches to enhance overall disease outcomes for patients with this condition. Methods: Quantitative reverse-transcription PCR was used to quantify the expression levels of microRNA (miR)-133a and miR-135a in 68 samples from 59 pediatric patients with AML. Dual-luciferase reporter transfection assay, Cell Counting Kit-8 assay, and western blot analysis were used to investigate the functions of miR-133a and miR-135a. Results: Our study found that all-trans-retinoic acid (ATRA) promoted the expression of miR-133a and miR-135a in AML cells, inhibited caudal type homeobox 2 (CDX2) expression, and subsequently inhibited the proliferation of AML cells. Additionally, miR-133a and miR-135a were highly expressed in patients with complete remission and those with better survival. Conclusions: miR-133a and miR-135a may play an antioncogenic role in pediatric AML through the ATRA-miRNA133a/135a-CDX2 pathway. They hold promise as potentially favorable prognostic indicators and novel therapeutic targets for pediatric AML.

M5 C regulator-mediated methylation modification patterns and tumor microenvironment infiltration characteristics in acute myeloid leukemia.

Recently, many studies have been conducted to examine immune response modification at epigenetic level, but the candidate effect of RNA 5-methylcytosine (m5 C) modification on tumor microenvironment (TME) of acute myeloid leukemia (AML) is still unknown at present. We assessed the patterns of m5 C modification among 417 AML cases by using nine m5 C regulators. Thereafter, we associated those identified modification patterns with TME cell infiltration features. Additionally, stepwise regression and LASSO Cox regression analyses were conducted for quantifying patterns of m5 C modification among AML cases to establish the m5 C-score. Meanwhile, we validated the expression of genes in the m5C-score model by qRT-PCR. Finally, the present work analyzed the association between m5 C-score and AML clinical characteristics and prognostic outcomes. In total, three different patterns of m5 C modification (m5 C-clusters) were identified, and highly differentiated TME cell infiltration features were also identified. On this basis, evaluating patterns of m5 C modification in single cancer samples was important for evaluating the immune/stromal activities in TME and for predicting prognosis. In addition, the m5 C-score was established, which showed a close relation with the overall survival (OS) of test and training set samples. Moreover, multivariate Cox analysis suggested that our constructed m5 C-score served as the independent predicting factor for the prognosis of AML (hazard ratio = 1.57, 95% confidence interval = 1.38-1.79, p < 1e-5 ). This study shows that m5 C modification may be one of the key roles in the formation of diversity and complexity of TME. Meanwhile, assessing the patterns of m5 C modification among individual cancer samples is of great importance, which provides insights into cell infiltration features within TME, thereby helping to develop relevant immunotherapy and predict patient prognostic outcomes.

Age-related dynamics in acute myeloid leukemia: Implications for prognosis, risk stratification, and treatment response

Abstract: BACKGROUND: Acute myeloid leukemia (AML) is a complex, heterogeneous disease driven by acquired somatic mutations. The presence of specific mutations advances stratification, treatment, and prognosis. Linear accumulation of mutations over time is a crucial factor in cancer development, particularly among elderly patients. Our recent study on gene rearrangement in AML revealed a significant association between age and adverse risk cases. AIM: The aim of this study was to examine the distribution of age, molecular characteristics, risk stratification, and treatment response based on age among patients with de novo AML in Iraq. PATIENTS AND METHODS: A prospective cohort study enrolled 115 Iraqi adult patients diagnosed with de novo AML using morphology and flow cytometry from December 2020 to May 2022. The Leukemia Q-Fusion Screening Kit, employing multiplex reverse transcription–real-time quantitative polymerase chain reaction with 30 gene rearrangements, was employed for the identification of gene rearrangement. The patients received care and follow-up at the Hematology Unit of Baghdad Teaching Hospital in Medical City. Ethical approval from the College of Medicine’s Ethical Committee at the University of Baghdad was secured before commencing the research, ensuring adherence to ethical standards throughout the study. RESULTS: The age distribution exhibited a bimodal pattern, with a mean of 45.1 ± 17.5 years, ranging from 18 to 84 years, and a median of 46 years. A total of 39.1% of patients were diagnosed with AML before the age of 35 years, while 43% were diagnosed after the age of 51 years. AML patients with RARA mutations, RUNX1::RUNX1T1 alterations, and NPM1 mutations were predominantly observed in younger individuals, as well as those diagnosed with AML defined by differentiation. Conversely, KMT2A rearrangements were more prevalent among older age groups, with a statistically significant difference in the distribution of AML classifications according to the World Health Organization (WHO) by age categories (P = 0.001). The risk stratification based on age and response assessment showed a notable higher risk profile observed among elderly patients that was associated with adverse risk and poorer response and mortality (P &lt; 0.05). The prediction of treatment response accuracy rate was improved by adding age to the WHO classification and ELN 2022 risk stratification (73.5%–87.9%). CONCLUSION: Age significantly influences AML prognosis and treatment response. Incorporating age into risk stratification improves accuracy. Tailored approaches considering age are vital for optimizing AML management and outcomes.

Variability in the perception of palliative care and end-of-life care among hematology professionals from the same reference center in Bahia, Brazil: A descriptive cross-sectional study.

There are several illness-specific cultural and system-based barriers to palliative care (PC) integration and end-of-life (EOL) care in the field of oncohematology. This study aimed to investigate the variability in the perceptions of PC and EOL care. A cross-sectional study was conducted in the Hematology Division of our University Hospital in Salvador, Bahia, Brazil. Twenty physicians responded to a sociodemographic questionnaire and an adaptation of clinical questionnaires used in previous studies from October to December 2022. The median age of the participants was 44 years, 80% of the participants identified as female, and 75% were hematologists. Participants faced a hypothetical scenario involving the treatment of a 65-year-old female with a poor prognosis acute myeloid leukemia refractory to first-line treatment. Sixty percent of the participants chose to follow other chemotherapy regimens, whereas 40% opted for PC. Next, participants considered case salvage for the patient who developed septic shock following chemotherapy and were prompted to choose their most probable conduct, and the conduct they thought would be better for the patient. Even though participants were from the same center, we found a divergence from the most probable conduct among 40% of the participants, which was due to personal convictions, legal aspects, and other physicians' reactions. We found considerable differences in the perception of PC and EOL care among professionals, despite following the same protocols. The study also demonstrated variations between healthcare professionals' beliefs and practices and persistent historical tendencies to prioritize aggressive interventions.

Identification of cell surface markers for acute myeloid leukemia prognosis based on multi-model analysis.

Given the extremely high inter-patient heterogeneity of acute myeloid leukemia (AML), the identification of biomarkers for prognostic assessment and therapeutic guidance is critical. Cell surface markers (CSMs) have been shown to play an important role in AML leukemogenesis and progression. In the current study, we evaluated the prognostic potential of all human CSMs in 130 AML patients from The Cancer Genome Atlas (TCGA) based on differential gene expression analysis and univariable Cox proportional hazards regression analysis. By using multi-model analysis, including Adaptive LASSO regression, LASSO regression, and Elastic Net, we constructed a 9-CSMs prognostic model for risk stratification of the AML patients. The predictive value of the 9-CSMs risk score was further validated at the transcriptome and proteome levels. Multivariable Cox regression analysis showed that the risk score was an independent prognostic factor for the AML patients. The AML patients with high 9-CSMs risk scores had a shorter overall and event-free survival time than those with low scores. Notably, single-cell RNA-sequencing analysis indicated that patients with high 9-CSMs risk scores exhibited chemotherapy resistance. Furthermore, PI3K inhibitors were identified as potential treatments for these high-risk patients. In conclusion, we constructed a 9-CSMs prognostic model that served as an independent prognostic factor for the survival of AML patients and held the potential for guiding drug therapy.

A Comprehensive Metabolism-Related Gene Signature Predicts the Survival of Patients with Acute Myeloid Leukemia.

(1) Background: Acute myeloid leukemia (AML) is a clonal malignancy with heterogeneity in genomics and clinical outcome. Metabolism reprogramming has been increasingly recognized to play an important role in the leukemogenesis and prognosis in AML. A comprehensive prognostic model based on metabolism signatures has not yet been developed. (2) Methods: We applied Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) normalization to establish a metabolism-related prognostic gene signature based on glycolysis, fatty acid metabolism, and the tricarboxylic acid cycle gene signatures. The Cancer Genome Atlas-Acute Myeloid Leukemia-like (TCGA-LAML) cohort was set as the training dataset for model construction. Three independent AML cohorts (GSE37642, GSE10358, and GSE12417) combined from Gene Expression Omnibus (GEO) datasets and the Beat-AML dataset were retrieved as two validation sets to test the robustness of the model. The transcriptome data and clinic information of the cohorts were enrolled for the analysis. (3) Results: Divided by the median value of the metabolism risk score, the five-year overall survival (OS) of the high-risk and low-risk groups in the training set were 8.2% and 41.3% (p < 0.001), respectively. The five-year OS of the high-risk and low-risk groups in the combined GEO cohort were 25.5% and 37.3% (p = 0.002), respectively. In the Beat-AML cohort, the three-year OS of the high-risk and low-risk groups were 16.2% and 40.2% (p = 0.0035), respectively. The metabolism risk score showed a significantly negative association with the long-term survival of AML. Furthermore, this metabolism risk score was an independent unfavorable factor for OS by univariate analysis and multivariate analysis. (4) Conclusions: Our study constructed a comprehensive metabolism-related signature with twelve metabolism-related genes for the risk stratification and outcome prediction of AML. This novel signature might contribute to a better use of metabolism reprogramming factors as prognostic markers and provide novel insights into potential metabolism targets for AML treatment.

TLR3 agonism augments CD47 inhibition in acute myeloid leukemia.

CD47-SIRPa is a myeloid check point pathway that promotes phagocytosis of cells lacking markers for self-recognition. Tumor cells can overexpress CD47 and bind to SIRPa on macrophages, preventing phagocytosis. CD47 expression is enhanced and correlated with a negative prognosis in acute myeloid leukemia (AML), with its blockade leading to cell clearance. ALX90 is an engineered fusion protein with high affinity for CD47. Composed of the N-terminal D1 domain of SIRPα genetically linked to an inactive Fc domain from human immunoglobulin (Ig) G, ALX90 is designed to avoid potential toxicity of CD47-expressing red blood cells. Venetoclax (VEN) is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore apoptosis in malignant cells. In AML, VEN is combined with azanucleosides to induce superior remission rates, however treatment for refractory/relapse is an unmet need. We questioned whether the anti-tumor activity of a VENbased regimen can be augmented through CD47 inhibition (CD47i) in AML and how this triplet may be enhanced. Human AML cell lines were sensitive to ALX90 and its addition increased efficacy of a VEN plus azacitidin (VEN+AZA) regimen in vivo. However, CD47i failed to clear bone marrow tumor burden in PDX models. We hypothesized that the loss of resident macrophages in the bone marrow in AML reduced efficiency of CD47i. Therefore, we attempted to enhance this medullary macrophage population with agonism of TLR3 via polyinosinic:polycytidylic acid (poly(I:C)), which led to expansion and activation of medullary macrophages in in vivo AML PDX models and potentiated CD47i. In summary, the addition of poly(I:C) can enhance medullary macrophage populations to potentiate the phagocytosis merited by therapeutic inhibition of CD47.

Potential Biomarkers for Diagnosis and Prognosis of Acute Myeloid Leukemia

For many years, cancer has affected the global population from an economic, social and political point of view and, in most cases, it is a malignant tumor with serious consequences for patients. The objective of this study is to answer the potential biomarkers for the diagnosis and prognosis of acute myeloid leukemia. Therefore, this is an exploratory, descriptive bibliographic study with a qualitative approach. The data were collected from a bibliometric survey carried out during a study of scientific production on the proposed topic from 2013 to 2023. After searching for articles, 210 articles were found on the PubMed platform, and no results were found for the key suggested by word in other databases. Among the 210 articles, 28 articles were selected for review. In this way, we seek to analyze which biomarkers have been addressed in the last 10 years in the scientific literature, thus aiming to demonstrate possible targets for new research. We divide our research into genes that are promising biomarkers for diagnosis and/or prognosis and the role of miRNAs as biomarkers.

MicroRNA-based therapies: Revolutionizing the treatment of acute myeloid leukemia.

MicroRNAs (miRNAs) are small noncoding epigenetic regulators that exert critical significance by influencing target mRNAs and governing gene expression patterns and cellular signaling pathways. miRNAs play a pivotal role in a wide array of biological processes, including cell differentiation, proliferation, and survival. Numerous miRNAs contribute to tumorigenesis and cancer progression by promoting tumor growth, angiogenesis, invasion, and immune evasion, while others exert tumor suppressive effects. From a clinical perspective, it has been demonstrated that numerous miRNAs are related to the prognosis in acute myeloid leukemia (AML) patients. They hold the potential to be utilized as biomarkers, aiding in improved treatment decision-making. Moreover, a number of preclinical investigations have offered compelling evidence to create novel treatment approaches that target miRNAs in AML. This review highlights the clinical significance of miRNAs in the diagnosis, prognosis, and treatment response of adult patients with AML.

A prognostic model based on prognosis-related ferroptosis genes for patients with acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is a heterogeneous disorder with an unpredictable prognosis. Ferroptosis, the iron-dependent cell death program, could serve as an alternative for overcoming drug resistance. However, its effect on AML remains largely unclear. Methods: We collected RNA sequencing data and relevant clinical information of AML patients from The Cancer Genome Atlas to construct a prognosis prediction model. Risk score was calculated with eight prognosis-related ferroptosis genes (PRFGs) discovered through univariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. A nomogram was constructed by incorporating LASSO risk score, age, and cytogenetic risk based on univariate/multivariate Cox regression. Results: Of the 33 AML PRFGs identified from the TCGA-derived dataset, 8 genes were used to construct a gene signature to predict AML prognosis. Principal component analysis and heatmap showed significant differences between the low and high risk score groups. Next, LASSO risk score, age, and cytogenetic risk were incorporated into the nomogram to predict the overall survival (OS) of AML patients. According to survival analysis, patients with a low risk score had markedly increased OS as compared to those with a high risk score. Based on the results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, the differences between the two risk groups showed a close relationship with immune-related pathways and membrane transportation. The analysis of tumor-infiltrating immune cells and immune checkpoints revealed that the immunosuppressive tumor microenvironment possibly facilitated different prognostic outcomes between the two groups. Gene expression analyses showed that the mRNA expression levels of PARP1 and PARP3 (PARPs) were closely related to the different clinical subgroups and the analyzed OS in AML patients. Finally, the PARP inhibitor talazoparib and the ferroptosis inducer erastin exerted a synergistic anti-proliferative effect on AML cells. Conclusion: We constructed a nomogram by incorporating PRFGs, and the constructed nomogram showed a good performance in AML patient stratification and prognosis prediction. The combination of PARP inhibitors with ferroptosis inducers could be a novel treatment strategy for treating AML patients.

Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations

Epigenetic regulators, such as the polycomb repressive complex 2 (PRC2), play a critical role in both normal development and carcinogenesis. Mutations and functional dysregulation of PRC2 complex components, such as EZH2, are implicated in various forms of cancer and associated with poor prognosis. This study investigated the epigenetic vulnerabilities of acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative disorders (MDS/MPN) by performing a chemical probe screen in patient cells. Paradoxically, we observed increased sensitivity to EZH2 and embryonic ectoderm development (EED) inhibitors in AML and MDS/MPN patient cells harboring EZH2 mutations. Expression analysis indicated that EZH2 inhibition elicited upregulation of pathways responsible for cell death and growth arrest, specifically in patient cells with mutant EZH2. The identified EZH2 mutations had drastically reduced catalytic activity, resulting in lower cellular H3K27me3 levels, and were associated with decreased EZH2 and PRC2 component EED protein levels. Overall, this study provides an important understanding of the role of EZH2 dysregulation in blood cancers and may indicate disease etiology for these poor prognosis AML and MDS/MPN cases.

De novo drug designing coupled with brute force screening and structure guided lead optimization gives highly specific inhibitor of METTL3: a potential cure for Acute Myeloid Leukaemia

Expression of METTL3, a SAM dependent methyltransferase, which deposits m6A on mRNA is linked to poor prognosis in Acute Myeloid Leukaemia and other type of cancers. Down regulation of this epitranscriptomic regulator has been found to inhibit cancer progression. Silencing the methyltransferase activity of METTL3 is a lucrative strategy to design anticancer drugs. In this study 3600 commercially available molecules were screened against METTL3 using brute force screening approach. However, none of these compounds take advantage of the unique Y-shaped binding cavity of the protein, raising the need for de novo drug designing strategies. As such, 125 branched, Y-shaped molecules were designed by “stitching” together the chemical fragments of the best inhibitors that interact strongly with the METTL3 binding pocket. This results in molecules that have the three-dimensional structure and functional groups which enable it to fit in the METTL3 cavity like fingers in a glove, having unprecedented selectivity and binding affinities. The designed compounds were further refined based on Lipinski’s rule, docking score and synthetic accessibility. The molecules faring well in these criteria were simulated for 100 ns to check the stability of the protein inhibitor complex followed by binding free energy calculation.Communicated by Ramaswamy H. Sarma

The Effects of Resveratrol, Gallic Acid, and Piperine on the Expression of miR-17, miR-92b, miR-181a, miR-222, BAX, BCL-2, MCL-1, WT1, c-Kit, and CEBPA in Human Acute Myeloid Leukemia Cells and Their Roles in Apoptosis.

MicroRNAs (miRs) play a crucial role in the leukemogenesis and the prognosis of acute myeloid leukemia (AML). This study investigated the therapeutic effects of resveratrol, gallic acid, and piperine as natural anticancer agents on the HL-60 cell line and their roles in apoptosis. In this experimental study, quantitative analysis of miRs, including miR-17, miR-92b, miR-181a, and miR-222, were performed in 150 newly diagnosed patients with AML by real-time PCR assay. HL-60 cell viability as well as the expression of miRs, BAX, BCL-2, MCL-1, WT1, c-Kit, and CEBPA, were also assessed after transfection with the LNA-miRs and treatment with resveratrol, gallic acid, and piperine. The expression of miR-17 and miR-181a decreased significantly in LNA-anti-miRs. Although HL-60 cell viability decreased in LNA-anti-miR-222, miR-17, and miR-92b, blockade of miR-181a increased the cell viability. Besides, the cell viability increased merely in the piperine-treated group. Compared to untreated cells, miR-17 and miR-92b expression significantly increased in gallic acid- and resveratrol-treated cells. In HL-60 cells treated with resveratrol, gallic acid, and piperine, the expression of miR-181a was also increased significantly. The expression of BAX was also increased in resveratrol and piperine-treated groups. Compared to untreated cells, the expression of c-Kit increased significantly in the piperine-treated group; however, it decreased in the resveratrol-treated group. LNA-anti-miRs may be a promising agent for the treatment of AML. All three compounds used in this study showed anticancer effects, which can exert the desired outcome in patients with AML.