Expression In Acute Myeloid Leukemia Research Articles

Research progress on DNMT3A gene expression in Acute myeloid leukemia

DNA methylation is an important epigenetic regulatory mechanism which plays a crucial role in cell differentiation and development. Its function is closely related to DNA methyltransferase 3 alpha (DNMT3A), which can affect gene expression and stem cell differentiation. The mutation rate of the DNMT3A gene is relatively high in Acute myeloid leukemia (AML), but its type and pathogenic mechanism are not yet clear. Further research on DNMT3A may help to identify its pathogenic targets and provide a basis for precise treatment of AML. This article has provided a review for the research progress on the expression of the DNMT3A gene in AML.

Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy

Malignant growth relies on rapid protein synthesis frequently leading to endoplasmic reticulum (ER) overload and accumulation of unfolded or misfolded protein in this cellular compartment. In the ER, protein homeostasis is finely regulated by a mechanism called the unfolded protein response (UPR), involving the activation of signalization pathways mediated by three transmembrane proteins, namely PERK, IRE1 and ATF6. IRE1 endoribonuclease activation leads in particular to the splicing of the cytosolic mRNA encoding the key UPR-specific transcription factor XBP1s. Our study shows that sustained activation of XBP1s expression in acute myeloid leukemia (AML) cells induces apoptosis in vitro and in vivo, whereas a moderate XBP1s expression sensitizes cells to chemotherapeutic treatments. ChIP-seq experiments identified specific XBP1s target genes including the MIR22HG lncRNA, the precursor transcript of microRNA-22-3p. miR-22-3p upregulation by XBP1s or forced expression of miR-22 significantly decreases cell’s viability and sensitizes leukemic cells to chemotherapy. We found that miR-22-3p intracellular effects result at least partially from the targeting of the mRNA encoding the deacetylase sirtuin-1 (SIRT1), a well-established pro-survival factor. Therefore, this novel XBP1s/miR-22/SIRT1 axis identified could play a pivotal role in the proliferation and chemotherapeutic response of leukemic cells.

Acute myeloid leukemia stem cell signature gene EMP1 is not an eligible therapeutic target.

Relapse in pediatric acute myeloid leukemia (pedAML) patients is known to be associated with residual leukemic stem cells (LSC). We have previously shown that epithelial membrane protein 1 (EMP1) is significantly overexpressed in LSC compared to hematological stem cell fractions. EMP1 was also documented as part of the 17-gene stemness score and a 6-membrane protein gene score, both correlating high EMP1 expression with worse overall survival. However, its potential as a therapeutic target in pedAML is still unexplored. Association analyses of EMP1 expression with clinical and molecular AML characteristics were performed. Expression of EMP1 was evaluated in pedAML and cord blood samples. Expression in normal blood cells and tissues was evaluated by flow cytometry and immunohistochemistry, respectively. In silico analyses showed variable mRNA expression of EMP1 in multiple pedAML datasets, and a significant correlation between high EMP1 transcript levels and the presence of inv(16). Flow cytometry showed overexpression of EMP1 in pedAML samples, as well as expression in normal blood subsets. Importantly, immunohistochemistry revealed EMP1 expression in multiple normal tissues. Although EMP1 presents as an interesting membrane-associated target in pedAML, its abundant expression in normal blood cells and tissues will impede it from further exploration as a therapeutic target. EMP1 is highly expressed in multiple cancer types, but expression in acute myeloid leukemia (AML) and normal tissues is unexplored. As EMP1 is investigated in other cancer types, expression in normal tissues and blood cells is relevant in predicting the success of EMP1-targeted therapies. In this study, we showed expression of EMP1 in multiple tissues, predicting high on-target off-tumor toxicity, which will warn other researchers of possible toxicities when generating EMP1-targeted therapy. Finally, we showed that high EMP1 expression is associated with better overall survival of pediatric AML patients, reducing the need for EMP1-targeted therapy.

Reverse Phase Proteomic Array Profiling of Asparagine Synthetase Expression in Newly Diagnosed Acute Myeloid Leukemia.

Asparaginase-based therapy is a cornerstone in acute lymphoblastic leukemia (ALL) treatment, capitalizing on the methylation status of the asparagine synthetase (ASNS) gene, which renders ALL cells reliant on extracellular asparagine. Contrastingly, ASNS expression in acute myeloid leukemia (AML) has not been thoroughly investigated, despite studies suggesting that AML with chromosome 7/7q deletions might have reduced ASNS levels. Here, we leverage reverse phase protein arrays to measure ASNS expression in 810 AML patients and assess its impact on outcomes. We find that AML with inv(16) has the lowest overall ASNS expression. While AML with deletion 7/7q had ASNS levels slightly lower than those of AML without deletion 7/7q, this observation was not significant. Low ASNS expression correlated with improved overall survival (46 versus 54 weeks, respectively, p = 0.011), whereas higher ASNS levels were associated with better response to venetoclax-based therapy. Protein correlation analysis demonstrated association between ASNS and proteins involved in methylation and DNA repair. In conclusion, while ASNS expression was not lower in patients with deletion 7/7q as initially predicted, ASNS levels were highly variable across AML patients. Further studies are needed to assess whether patients with low ASNS expression are susceptible to asparaginase-based therapy due to their inability to augment compensatory ASNS expression upon asparagine depletion.

Role of miR-424 expression in acute myeloid leukemia and correlation with nucleophosmin 1 (NPM1) mutations modyfied

Role of miR-424 expression in acute myeloid leukemia and correlation with nucleophosmin 1 (NPM1) mutations modyfied

Role of miR-155 expression in acute myeloid leukemia and correlation with nucleophosmin 1 (NPM1) mutations modyfied

Role of miR-155 expression in acute myeloid leukemia and correlation with nucleophosmin 1 (NPM1) mutations modyfied

Prognostic implications of cGAS and STING gene expression in acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the most threatening hematological malignances. cGAS-STING pathway plays an important role in tumor immunity and development. However, the prognostic role of cGAS-STING pathway in AML remains unknown. Firstly, The expression of cGAS and STING was analyzed by bioinformatics analysis. Subsequently, Bone marrow samples were collected from 120 AML patients and 15 healthy individuals in an independent cohort. The cGAS and STING expression was significantly elevated in AML patients compared with healthy controls. Patients with high cGAS and STING expression had a higher NRAS/KRAS mutation rate and lower complete remission (CR) rate. High cGAS and STING expression was significantly associated with lower overall survival (OS) and disease-free survival (DFS). Our findings revealed that the expression levels of cGAS and STING in AML are elevated. High expression of cGAS and STING correlated with worse OS and DFS and may be a useful biomarker for inferior prognosis in AML patients.

Prognostic Significance of Dual-Specificity Phosphatase 23 Expression in Acute Myeloid Leukemia.

Recently, an increasing number of studies have suggested dual-specificity phosphatase 23 (DUSP23) is a critical factor in the development of diffuse connective tissue disease and may be a valuable biomarker for primary human cancers. However, there is a lack of comprehensive studies on the prognostic significance of DUSP23 expression in acute myeloid leukemia (AML). RNA sequencing data from The Cancer Genome Atlas (TCGA) (AML = 173), Genotype-Tissue Expression (GTEx) (healthy controls = 70) and GEO (AML = 461, healthy controls = 76) databases were used to compare DUSP23 expression between AML patients and healthy controls. The overall survival (OS) of DUSP23 in AML was evaluated using Kaplan-Meier Cox regression. Furthermore, univariate Cox regression and multivariate Cox regression analysis were used to determine whether DUSP23 was an independent prognostic factor for AML. We then verified the expression level and prognostic significance of DUSP23 in our cohort (AML = 128, healthy controls = 31). In addition, functional enrichment analysis of DUSP23-related DEGs was performed through gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network analysis. The expression level of DUSP23 is significantly higher in AML patients than in healthy controls in TCGA, GTEx, GEO databases and our cohort. By multivariate analysis, high expression of DUSP23 is a poor prognostic indicator of OS in the TCGA database. Next, we verified the role of DUSP23 as an adverse prognostic biomarker in our cohort. Enrichment analysis of related genes showed that DUSP23 may regulate important signal pathways in hematological tumors including the MAPK pathways. It is suggested by the PPI network that DUSP23, along with IMP3, MRPL4, MRPS12, POLR2L, and ATP5F1D may play a role in the process of AML. The study demonstrated high expression of DUSP23 could serve as a poor independent prognostic biomarker in AML.

Clinical significance of decreased or loss of ABO blood group expression in acute myeloid leukaemia: A single-centre retrospective study.

Decreased or loss of ABO blood group antigen expression has been observed in acute myeloid leukaemia (AML) patients. We studied the clinical significance of this group in AML patients. This was a retrospective, single-centre cohort study in which the data were retrieved from April 2009 to December 2019. A total of 1592 AML patients with normal ABO blood group antigen (Group I) and 65 patients of decreased or loss of ABO blood group antigen (Group II) group were enrolled. Data were collected at the time of initial admission for pathological diagnosis. To interrogate the underlying mechanism, publicly available The Cancer Genome Atlas AML data were downloaded. Group II consisted of 3.9% (65/1657) of AML patients. The 90-day survival (D90) probability was higher for Group II with a mean survival of 86.4 days compared to 80.6 days for Group I (p = 0.047). Group II had higher haematocrit (28.6 vs. 27.4%) and lower d-dimer, fibrinogen degradation production and C-reactive protein. Publicly available data revealed that among 11 CpG methylation sites within the ABO gene, 4 sites with elevated methylation level were associated with improved D90 survival probability and demonstrated an inverse correlation with ABO gene expression. Lower expression of the ABO gene showed improved survival trends for D90 (p = 0.058) and 180-day survival (p = 0.072). AML with decreased expression or loss of ABO blood group showed better early survival during D90. Transfusion support for this subgroup of AML patients should be meticulously performed considering serum typing.

Casein Kinase II Inhibitor Sensitizes the Anti-Tumor Effect of EZH2 Inhibitor By Suppressing FOSL1 Expression in Acute Myeloid Leukemia

Background More effective combination therapy is emerging needed owing to the high mortality and poor outcome in acute myeloid leukemia (AML). The genomic amplification and overexpression of Enhancer of zeste homolog 2 (EZH2) occur in AML patients, and high expression of the Casein kinase 2 (CK2) is associated with poor survival in AML patients. Both EZH2 inhibitor and CK2 inhibitors are reported to inhibit cell proliferation and induce apoptosis in AML, however, the anti-leukemia effect of EZH2 inhibitor in combination with CK2 inhibitor has not been reported. The present study aims to investigate the effect of the combination of the EZH2 inhibitor DZNeP with CK2 inhibitor CX4945 in AML and possible underlying mechanisms. Methods A total of 40 newly diagnosed AML patients and 40 bone marrow control from healthy donors were obtained from our institute with the approval of the Ethics Committee. Cell Counting Kit-8 assay (CCK8), Cell cycle assay, and apoptosis assays were applied in THP-1 AML cells treated with control, DZNeP, CX4945, and CX4945+DZNeP. Global transcriptome analysis by RNA-seq was performed in U937 cells treated with 2μM DZNeP; 12.5μM CX4945 or vehicle for 48 hours. FOSL1 mRNA level was examined by qPCR; R2 genomics analysis and visualization application were used for comparison of the expression difference and the Kaplan-Meier overall survival analysis was conducted by the Gene Expression Profiling Interactive Analysis (GEPIA) platform. Results DZNeP only has little effect on cell proliferation arrest in THP-1 cells, but it significantly sensitized the effect of CX4945, and CalcuSyn analysis showed the synergistic effect of the CX4945+DZNeP (Fig.1A). The treatment of CX4945+DZNeP combination induced the G0/G1 phase arrest in THP-1 cells versus single-drug control (Fig. 1B). The combination also significantly increased the % of the apoptotic cells in THP-1 cells as well as the AML-5b primary cells from the patient compared to single-drug controls (p<0.0001) (Fig.1C). These data indicate the synergistic anti-tumor effect of CX4945+DZNep combination in AML. To understand the molecular mechanism underlying the synergy, the global transcriptome was identified in U937 cells. The significantly different expression genes (DEGs) were identified upon CX4945 treatment (∣log2FC∣>1.5, FDR<0.05), or DZNeP treatment (∣log2FC∣>1.0, FDR<0.05) versus vehicle-control; and 1908 overlapped DEGs are identified upon either drug treatment, in which 596 were intersected (429 genes changed in the same direction but 167 changed in the opposite (Fig. 1D). KEGG enrichment analyses showed the overlapped DEGs upon the drug treatment mainly involved in cell cycle, DNA replication, and MAPK signaling pathway. (Fig.1E). It is worth noting that FOSL1 is dramatically downregulated in U937 cells upon treatment of either DZNeP or CX4945 (Fig1.D); and qPCR data showed that the mRNA level of FOSL1 is significantly downregulated by CX4945+DZNeP, DZNeP or CX4945 compared to the vehicle control (p<0.0001) in THP-1 cells (Fig. 1F). These data indicated that the combination exerts its anti-tumor effect by down-regulation of FOSL1 expression in AML. FOSL1 is a key component of the AP-1 transcriptional complex, and overexpression of FOSL1 is associated with invasion, migration, proliferation, and stemness in human solid cancers. We also examined the FOSL1 mRNA level in 40 newly diagnosed patients with AML versus 40 normal bone marrow controls. Results showed the mRNA level of FOSL1 is significantly higher in AML patients than that of normal controls (p<0.001) (Fig1.G). Metadata analysis showed that FOSL1 high expression is associated with short overall survival (p=0.033) (Fig.1H). These results not only suggested the oncogenic role of FOSL1 in AML but also further supported the CX4945+DZNeP combination-induced anti-tumor effect mediated by suppressing FOSL1 expression in AML. The mechanism model is summarized in Fig. 1E. Conclusion The combination of EZH2 inhibitor DZNeP and CK2 inhibitor CX4945 exerts a potent synergistic effect on proliferation arrest, cell cycle arrest, and apoptosis in AML by suppressing FOSL1 expression. Our results reveal the oncogenic role of FOSL1 in AML. Our data also provide experimental hints for the potential clinical trial of the novel combination in AML patients.

Prevalence and clinical impact of CD56 and T-cell marker expression in acute myeloid leukaemia: A single-centre retrospective analysis.

Flow cytometry-based immunophenotyping is a mainstay of diagnostics in acute myeloid leukaemia (AML). Aberrant CD56 and T-cell antigen expression is observed in a fraction subset of AML cases, but the clinical relevance remains incompletely understood. Here, we retrospectively investigated the association of CD56 and T-cell marker expression with disease-specific characteristics and outcome of 324 AML patients who received intensive induction therapy at our centre between 2011 and 2019. We found that CD2 expression was associated with abnormal non-complex karyotype, NPM1 wild-type status and TP53 mutation. CD2 also correlated with a lower complete remission (CR) rate (47.8%vs. 71.6%, p=0.03). CyTdT and CD2 were associated with inferior 3-year event-free-survival (EFS) (5.3%vs. 33.5%, p=0.003 and 17.4%vs. 33.1%, p=0.02, respectively). CyTdT expression was also correlated with inferior relapse-free survival (27.3%vs. 48.8%, p=0.04). In multivariable analyses CD2 positivity was an independent adverse factor for EFS (HR 1.72, p=0.03). These results indicate a biological relevance of aberrant T-cell marker expression in AML and provide a rationale to further characterise the molecular origin in T-lineage-associated AML.

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.

Identification and validation of a prognostic risk-scoring model based on the level of TIM-3 expression in acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by an unfavorable prognosis due to the presence of self-renewing leukemic stem cells (LSCs). The presence of T-cell immunoglobulin mucin-3 (TIM-3) on the surface of LSCs has been observed in various types of human AML, exerting an impact on the prognostic outcome. Exploring the hub genes associated with varying levels of TIM-3 expression offers a valuable approach to enhance our understanding of the underlying mechanisms involving TIM-3 and to identify potential prognostic indicators in AML. Nevertheless, to date, no research studies have reported a prognostic model that relies on the level of TIM-3 expression. In our study, we screen the hub-genes based on different expression level of TIM-3 through WGCNA. The prognostic risk-scoring model was constructed based on hub-genes. The results show the risk prognostic model has extraordinary ability to predict prognosis in both the training and validation sets. The high-risk group present poor prognosis with mutation of NPM1, TP53 (Multiple Hit) and FLT3(multiple hit), while IDH2 (Missense Mutation), MUC16 (Multiple Hit/Missense Mutation) occur mutation in low-risk group presenting favorite prognosis than high-risk group. Leukocyte cell–cell adhesion, regulation of T cell activation and I-κB kinase/NF-κB signaling enriched in high-risk group, involving in HSCs or LSCs anchoring to BM, which implicated in LSCs survival and chemotherapy resistance. B7-H3 (CD276) and CD276 would be the potential immune targets in high-risk group. The risk score model may help in distinguishing immune and molecular characteristics, predicting patient outcomes.

Identification of TIM-3 Expression in Acute Myeloid Leukemia: Clinical and Laboratory Correlation

Abstract Background Acute myeloid leukemia (AML) is an aggressive highly heterogenous hematological malignancy associated with poor prognosis and high mortality rate. Both cancer cells and immune cells participate in tumor initiation, growth and progression and might affect clinical outcomes. Indeed, leukemic cells exploit a variety of mechanisms to evade immune response, leading to disease progression and relapse. T-cell immunoglobulin and mucin domain 3 (TIM-3), an immune checkpoint molecule, is expressed not only on immune cells but also on leukemic stem cells (LSCs) in AML. Studies relating to TIM-3 function in AML are limited, and the role of TIM3 in maintaining leukemic stem cells and contributing to the suppression of the anti-tumor immune response is still poorly understood. Aim of the Work To investigate TIM-3 expression in patients with AML and explore the impact of its expression on the clinico-laboratory characteristics and prognostic behavior of denovo-AML patients. Methods A total of 45 patients newly diagnosed AML patients were tested for TIM-3 expression by flowcytometry at diagnosis. Results TIM-3 was found to be over expressed in patients with AML with significant association with the different FAB subtypes (p = 0.010). TIM-3 positivity was negatively correlated with CD34 expression (p = 0.019.). However, no significant association between TIM-3 expression and extramedullary disease (EMD) as well as cytogenetic risk groups. Conclusion TIM-3 is overexpressed in AML patients. The prognostic value of TIM3 in AML is not clear and remains to be further explored.

Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Circular RNA PVT1 Regulates Cell Proliferation, Migration, and Apoptosis by Stabilizing c-Myc and Downstream Target CXCR4 Expression in Acute Myeloid Leukemia

This study aimed to investigate the role and mechanism of circular RNA PVT1 (circPVT1) in patients with acute myeloid leukemia (AML). The expression of circPVT1 in 23 patients with de novo AML (not acute promyelocytic leukemia, not APL) and cell lines were detected by RT-qPCR. Loss of function assays were carried out to explore the influence of silenced circPVT1 on the proliferation, migration, and apoptosis in the THP-1 cell line. CCK-8 assays, trans-well assays, and annexin V/PI staining assays were performed to assess proliferation, migration, and apoptosis, respectively. CircPVT1 was highly expressed in AML patients and myeloid cell lines compared to healthy controls. Higher expression of circPVT1 was related to shorter overall survival (OS) and relapse-free survival (RFS) in AML patients. Cell viability and migration were inhibited and apoptosis was increased when circPVT1 was knocked down in THP-1 cells. Knockdown of circPVT1 resulted in marked suppression of c-Myc protein with no significant change in mRNA levels. We also found that circPVT1 knockdown markedly increased the phosphorylation of c-Myc Thr-58, which was responsible for c-Myc degradation. Silencing of c-Myc caused a significant decrease in CXCR4 mRNA and protein expression, whereas the overexpression of c-Myc caused the opposite result, suggesting that CXCR4 is a target molecule of c-Myc. Finally, we found that overexpression of c-Myc could partially reverse circPVT1 knockdown-induced anti-tumor effects on THP-1 cells in vitro. Our findings showed that circPVT1 was highly expressed in AML patients and was related to shorter OS and RFS. CircPVT1 may exert an oncogenic effect in THP-1 cells by stabilizing c-Myc protein expression and downstream target CXCR4 expression. These data indicate that circPVT1 may be a promising therapeutic target for AML.

A new pathway for the transformation of AML in MDS: APA mechanism regulated by NUDT21 and RUNX1.

We have identified that NUDT21 plays a vital role in MDS transformations, while the transcription factor RUNX1 is essential for normal hematopoiesis, which is a high expression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), and we aim to explore the linkage between the two genes and new pathways for MDS transformation to AML. Prediction of RUNX1 expression levels and its relationship with NUDT21 in AML and MDS patients was performed using bioinformatics techniques and validated in patients. Using lentiviral packaging technology, NUDT21 knockdown and overexpression models were developed in AML and MDS cell lines. These models were validated using quantitative polymerase chain reaction (qPCR) and western blotting. The cell cycle, apoptosis, differentiation, and cytokines were examined by flow cytometry, CCK-8 analyzed proliferation, and the intracellular localization of NUDT21 and RUNX1 was examined by immunofluorescence. mRNA transcriptome sequencing was performed on THP-1, MUTZ-1, and Dapars analyzed SKM-1 cell lines and the sequencing data to observe the knockdown effect of NUDT21 on RUNX1. qPCR and western blot revealed a positive correlation between NUDT21 and RUNX1; both were located in the nucleus. Overexpression of NUDT21 reduced apoptosis, promoted cell proliferation, and possibly increased the invasive ability of cells. It also altered the APA site in the RUNX1 3'-UTRs region. NUDT21 regulates RUNX1 gene expression and promotes AML transformation in MDS through an APA mechanism.

Comprehensive analysis of ID genes reveals the clinical and prognostic value of ID3 expression in acute myeloid leukemia using bioinformatics identification and experimental validation

BackgroundDysregulation of inhibitor of differentiation/DNA binding (ID) genes is linked to cancer growth, angiogenesis, invasiveness, metastasis and patient survival. Nevertheless, few investigations have systematically determined the expression and prognostic value of ID genes in acute myeloid leukemia (AML).MethodsThe expression and clinical prognostic value of ID genes in AML were first identified by public databases and further validated by our research cohort.ResultsUsing public data, the expression of ID1/ID3 was markedly downregulated in AML, and the expression of ID2 was greatly upregulated in AML, whereas ID4 showed no significant difference. Among the ID genes, only ID3 expression may be the most valuable prognostic biomarker in both total AML and cytogenetically normal AML (CN-AML) and especially in CN-AML. Clinically, reduced ID3 expression was greatly associated with higher white blood cell counts, peripheral blood/bone marrow blasts, normal karyotypes and intermediate cytogenetic risk. In addition, low ID3 expression was markedly related to FLT3 and NPM1 mutations as well as wild-type TP53. Despite these associations, multivariate Cox regression analysis revealed that ID3 expression was an independent risk factor affecting overall survival (OS) and disease free survival (DFS) in CN-AML patients. Biologically, a total of 839 mRNAs/lncRNAs and 72 microRNAs were found to be associated with ID3 expression in AML. Importantly, the expression of ID3 with discriminative value in AML was further confirmed in our research cohort.ConclusionThe bioinformatics analysis and experimental verification demonstrate that low ID3 expression independently affects OS and DFS in patients with CN-AML, which might be seen as a potential prognostic indicator in CN-AML.

Nuclear Phase Separation Directs HOX Expression in Acute Myeloid Leukemia

Nuclear Phase Separation Directs HOX Expression in Acute Myeloid Leukemia

The prognostic role of C-KIT, TET1 and TET2 gene expression in Acute Myeloid Leukemia

Aimwas to assess the role of C-KIT, TET1 and TET2 expression in the diagnosis and prognosis of acute myeloblastic leukemia (AML).MethodsThe expression levels of C-KIT, TET1 and TET2 were assessed in the bone marrow (BM) aspirate of 152 AML patients compared to 20 healthy control using quantitative real-time polymerase chain reaction (qRT-PCR). Data were correlated with the clinico-pathological features of the patients, response to treatment, disease-free survival (DFS), and overall survival (OS) rates.ResultsC-KIT, TET1 and TET2 were significantly upregulated in AML patients [0.25 (0–11.6), 0.0113 (0–3.301), and 0.07 (0–4); respectively], compared to the control group [0.013 (0.005–0.250), P < 0.001, 0.001 (0–0.006), P < 0.001, and 0.02 (0.008–0.055), P = 0.019; respectively]. The sensitivity, specificity, and area under curve of of C-KIT were (48.7%, 100%, 0.855; respectively, P = 0.001), and that of TET1 were (63.4%, 100%, 0.897; respectively, P = 0.001), while that of TET2 were (56.8%, 100%, 0.766; respectively, P = 0.019). When combining the three markers, the sensitivity was 77.5%, however it reached the highest sensitivity (78.6%) and specificity (100%) when combining both c-KIT + TET1 together for the diagnosis of AML. C-KIT overexpression associated with shorter DFS (P = 0.05) and increased incidence of relapse (P = 0.019). Lymph nodes involvement [HR = 2.200, P = 0.005] is an independent risk factor for shorter OS rate of AML patients. Increased BM blast % [HR = 7.768, P = 0.002], and FLT3-ITD mutation [HR = 2.989, P = 0.032] are independent risk factors for shorter DSF rate of the patients.ConclusionC-KIT, TET1, and TET2 could be used as possible useful biomarkers for the diagnosis of AML.