Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia: a registry study.

Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (T max) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%-53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%-56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months-not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months-NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

Cuproptosis-related lncRNA signature as a prognostic tool and therapeutic target in diffuse large B cell lymphoma.

Cuproptosis is a newly defined form of programmed cell death that relies on mitochondria respiration. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis and metastasis. However, whether cuproptosis-related lncRNAs are involved in the pathogenesis of diffuse large B cell lymphoma (DLBCL) remains unclear. This study aimed to identify the prognostic signatures of cuproptosis-related lncRNAs in DLBCL and investigate their potential molecular functions. RNA-Seq data and clinical information for DLBCL were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Cuproptosis-related lncRNAs were screened out through Pearson correlation analysis. Utilizing univariate Cox, least absolute shrinkage and selection operator (Lasso) and multivariate Cox regression analysis, we identified seven cuproptosis-related lncRNAs and developed a risk prediction model to evaluate its prognostic value across multiple groups. GO and KEGG functional analyses, single-sample GSEA (ssGSEA), and the ESTIMATE algorithm were used to analyze the mechanisms and immune status between the different risk groups. Additionally, drug sensitivity analysis identified drugs with potential efficacy in DLBCL. Finally, the protein-protein interaction (PPI) network were constructed based on the weighted gene co-expression network analysis (WGCNA). We identified a set of seven cuproptosis-related lncRNAs including LINC00294, RNF139-AS1, LINC00654, WWC2-AS2, LINC00661, LINC01165 and LINC01398, based on which we constructed a risk model for DLBCL. The high-risk group was associated with shorter survival time than the low-risk group, and the signature-based risk score demonstrated superior prognostic ability for DLBCL patients compared to traditional clinical features. By analyzing the immune landscapes between two groups, we found that immunosuppressive cell types were significantly increased in high-risk DLBCL group. Moreover, functional enrichment analysis highlighted the association of differentially expressed genes with metabolic, inflammatory and immune-related pathways in DLBCL patients. We also found that the high-risk group showed more sensitivity to vinorelbine and pyrimethamine. A cuproptosis-related lncRNA signature was established to predict the prognosis and provide insights into potential therapeutic strategies for DLBCL patients.

Long non-coding RNA LOXL1-AS1: a potential biomarker and therapeutic target in human malignant tumors.

Long non-coding RNAs (lncRNAs) are transcripts that contain more than 200 nucleotides. Despite their inability to code proteins, multiple studies have identified their important role in human cancer through different mechanisms. LncRNA lysyl oxidase like 1 antisense RNA 1 (LOXL1-AS1), a newly discovered lncRNA located on human chromosome 15q24.1, has recently been shown to be involved in the occurrence and progression of various malignancies, such as colorectal cancer, gastric cancer, hepatocellular carcinoma, prostate cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, breast cancer, glioma, thymic carcinoma, pancreatic carcinoma. LOXL1-AS1 acts as competitive endogenous RNA (ceRNA) and via sponging various miRNAs, including miR-374b-5p, miR-21, miR-423-5p, miR-589-5p, miR-28-5p, miR-324-3p, miR-708-5p, miR-143-3p, miR-18b-5p, miR-761, miR-525-5p, miR-541-3p, miR-let-7a-5p, miR-3128, miR-3614-5p, miR-377-3p and miR-1224-5p to promote tumor cell proliferation, invasion, migration, apoptosis, cell cycle, and epithelial-mesenchymal transformation (EMT). In addition, LOXL1-AS1 is involved in the regulation of P13K/AKT and MAPK signaling pathways. This article reviews the current understanding of the biological function and clinical significance of LOXL1-AS1 in human cancers. These findings suggest that LOXL1-AS1 may be both a reliable biomarker and a potential therapeutic target for cancers.

Targeted delivery of HSP90 inhibitors for efficient therapy of CD44-positive acute myeloid leukemia and solid tumor-colon cancer.

Heat shock protein 90 (HSP90) is overexpressed in numerous cancers, promotes the maturation of numerous oncoproteins and facilitates cancer cell growth. Certain HSP90 inhibitors have entered clinical trials. Although less than satisfactory clinical effects or insurmountable toxicity have compelled these trials to be terminated or postponed, these results of preclinical and clinical studies demonstrated that the prospects of targeting therapeutic strategies involving HSP90 inhibitors deserve enough attention. Nanoparticulate-based drug delivery systems have been generally supposed as one of the most promising formulations especially for targeting strategies. However, so far, no active targeting nano-formulations have succeeded in clinical translation, mainly due to complicated preparation, complex formulations leading to difficult industrialization, incomplete biocompatibility or nontoxicity. In this study, HSP90 and CD44-targeted A6 peptide functionalized biomimetic nanoparticles (A6-NP) was designed and various degrees of A6-modification on nanoparticles were fabricated to evaluate targeting ability and anticancer efficiency. With no excipients, the hydrophobic HSP90 inhibitor G2111 and A6-conjugated human serum albumin could self-assemble into nanoparticles with a uniform particle size of approximately 200 nm, easy fabrication, well biocompatibility and avoidance of hepatotoxicity. Besides, G2111 encapsulated in A6-NP was only released less than 5% in 12 h, which may avoid off-target cell toxicity before entering into cancer cells. A6 peptide modification could significantly enhance uptake within a short time. Moreover, A6-NP continues to exert the broad anticancer spectrum of Hsp90 inhibitors and displays remarkable targeting ability and anticancer efficacy both in hematological malignancies and solid tumors (with colon tumors as the model cancer) both in vitro and in vivo. Overall, A6-NP, as a simple, biomimetic and active dual-targeting (CD44 and HSP90) nanomedicine, displays high potential for clinical translation.

Genetic variations in DNA excision repair pathway contribute to the chemosensitivity and prognosis of acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematologic malignancy with a high recurrence rate and poor long-term prognosis. DNA excision repair systems, such as base excision repair (BER) and nucleotide excision repair (NER), play a major role in maintaining genomic stability and integrity. Further intensive investigations are necessary to uncover additional AML prognosis loci. In this study, we analyzed 16 candidate SNPs within NER and BER pathways in AML patients. Our results showed the GT/GG genotype of the XPC rs2228001 polymorphism was significantly associated with WBC count in dominant models (OR = 0.41, 95 % CI = 0.18-0.96, p = 0.039). Additionally, the rs25487 and rs3213245 SNPs in the XRCC1 gene, in both co-dominant and dominant models, were significantly associated with PLT count in AML (p < 0.05). The GG genotype of rs1130409 in APEX1 was more prone to adverse cytogenetics in both the codominant and recessive models (p < 0.05). Furthermore, the GA genotypes of ERCC8 rs158572 in codominant model was significantly correlated with refractory group (p < 0.05). ERCC8 rs158572 and XRCC1 rs3213245 in both codominant and dominant models were significantly correlated with the MRD positivity (p < 0.05). Kaplan-Meier analysis revealed an link between overall survival (OS) and the co-dominant, dominant, and recessive models of rs2228001 in XPC. Additionally, patients with the GG and GT/GG genotype in the co-dominant, dominant model and recessive model in XPC rs2228001 exhibited significantly longer survival (p < 0.05). Multivariate Cox analyses indicated that rs2228001 in both co-dominant and dominant models were independent favorable factors impacting patient OS (OR < 1). Our findings suggest that genetic polymorphisms in DNA excision repair pathway genetic polymorphisms contribute to the chemosensitivity and prognosis of acute myeloid leukemia.

Efficacy and Safety of BTKis in Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of Bruton tyrosine kinase inhibitors (BTKis) for central nervous system lymphoma (CNSL). METHODS: A systematic review was carried out to identify relevant studies from the PubMed, Embase, Cochrane Library, Web of Science, WanFang, CNKI, and CBM databases. The studies included patients with CNSL who received BTKis and reported the overall response (OR), complete remission (CR), and partial response (PR). An overall effect analysis was performed using STATA 15.0. A random-effects model was utilized to calculate the pooled rates, and 95% confidence intervals (CI) were determined for all outcomes. RESULTS: A total of 21 studies involving 368 patients were included in the meta-analysis. For newly diagnosed CNSL, due to the small simple size, we conducted a quantitative description, and the ORR could reach up to 100%. For relapsed/refractory patients, the pooled ORR was 72% (95% CI: 64-80%, I2 = 54.89%, p = 0.00), with a pooled CR and PR of 43% (95% CI: 33-54%, I2 = 65.40%, p = 0.00) and 23% (95% CI: 13-35%, I2 = 78.05%, p = 0.00), respectively. Most adverse events were hematology-related and generally manageable. CONCLUSION: BTKis showed acceptable efficacy and safety in treating patients with CNSL. However, large and well-designed trials are still required to confirm BTKis as a treatment for CNSL.

Contribution of ApoB-100/SORT1-Mediated Immune Microenvironment in Regulating Oxidative Stress, Inflammation, and Ferroptosis After Spinal Cord Injury.

This study aims to explore the impacts of ApoB-100/SORT1-mediated immune microenvironment during acute spinal cord injury (SCI), and to investigate the potential mechanism. CB57BL/6 mice underwent moderate thoracic contusion injury to establish the SCI animal model, and received ApoB-100 lentivirus injection to interfere ApoB-100 level. Functional recovery was assessed using the Basso, Beattie, and Bresnahan (BBB) score and footprint analysis. Transmission electron microscopy was applied to observe the ultrastructure of the injured spinal cord tissue. Hematoxylin-eosin (HE) staining and Perls staining were conducted to assess histological changes and iron deposition. Biochemical factor and cytokines were detected using their commercial kits. M1/M2 macrophage markers were detected by immunofluorescence assay in vivo and by flow cytometry in vitro. HT22 neurons were simulated by lipopolysaccharide (LPS), followed by incubation with polarized macrophage medium to simulate the immune microenvironment of injured spinal cord in vitro. The local immune microenvironment is changed in SCI mice, accompanied with the occurrence of oxidative stress and the elevation of both M1 and M2 macrophages. Knockdown of ApoB-100 ameliorates oxidative stress and lipid disorder, and inhibits inflammation and ferroptosis in SCI mice. Importantly, knockdown of ApoB-100 can partly restrict M1 macrophages but does not change M2 macrophage proportion in SCI mice. Further, M1 macrophages are observed to attenuate the inflammatory response, oxidative stress, and ferroptosis levels of LPS-induced HT22 cells, which is further strengthened by SORT1 knockdown. Blockage of ApoB-100/SORT1-mediated immune microenvironment plays a protective role against SCI via inhibiting oxidative stress, inflammation, lipid disorders, and ferroptosis, providing novel insights of the targeted therapy of SCI.

Fragment-pair based drug molecule solubility prediction through attention mechanism.

The purpose of drug discovery is to identify new drugs, and the solubility of drug molecules is an important physicochemical property in medicinal chemistry, that plays a crucial role in drug discovery. In solubility prediction, high-precision computational methods can significantly reduce the experimental costs and time associated with drug development. Therefore, artificial intelligence technologies have been widely used for solubility prediction. This study utilized the attention layer in mechanism in the deep learning model to consider the atomic-level features of the molecules, and used gated recurrent neural networks to aggregate vectors between layers. It also utilized molecular fragment technology to divide the complete molecule into pairs of fragments, extracted characteristics from each fragment pair, and finally fused the characteristics to predict the solubility of drug molecules. We compared and evaluated our method with five existing models using two performance evaluation indicators, demonstrating that our method has better performance and greater robustness.

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation.

CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.

Treadmill exercise prevents the hyperexcitability of pyramidal neurons in medial entorhinal cortex in the 3xTg-AD mouse model of Alzheimer's disease.

Neuronal hyperactivity is a key abnormality in early stage Alzheimer's disease (AD). Medial entorhinal cortex (mEC) plays a vital role in memory function and is affected early in AD. Growing evidence indicates benefits of regular exercise on memory and cognitive function in humans with AD, although, the underlying mechanisms are not clear. Therefore, this study was designed to test the effects of 16 weeks treadmill exercise on spatial learning memory and the underlying cellular mechanisms in 6-month-old 3xTg-AD mice. Whole-cell patch clamp was used to examine neuronal intrinsic excitability, spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) of mEC layer II/III pyramidal neurons in the following groups: wild type (WT + sham), 3xTg-AD (AD+sham), WT receiving exercise (WT + Ex), and AD receiving exercise (AD+Ex). We found that at a behavioral level, treadmill exercise decreased working memory errors in radial arm maze (RAM) test in 6-month-old AD mice. At a cellular level, we found that treadmill exercise prevented the abnormal increase in mEC pyramidal neuron input resistance and action potential firing in 6-month-old 3xTg-AD mice compared with WT + sham and AD+Ex mice; further, sEPSC amplitude and frequency were normal in AD+Ex but overactive in AD+sham; additionally, GABAergic inhibition was normal in AD+Ex mice but reduced in AD+sham. In conclusion, our results indicate that treadmill exercise improves spatial learning memory and prevents network hyperexcitability in mEC by reducing pyramidal neuronal intrinsic excitability and normalizing excitatory and inhibitory synaptic transmission in 3xTg-AD mice.

Prognostic Value of PIK3R4 Expression and Its Correlation with Immune Cell Infiltration in the Diffuse Large B-cell Lymphoma Microenvironment.

Background: As a regulatory unit of class III phosphoinositide 3-kinase (PI3K), PIK3R4 is an important molecule involved in several malignant tumours, but the role and molecular mechanism of PIK3R4 in diffuse large B-cell lymphoma (DLBCL) is still unclear. Methods: Multiple bioinformatics analyses were used to investigate the role and potential mechanisms of PIK3R4 in DLBCL. Quantitative real-time polymerase chain reaction (qRT‒PCR) was performed to determine the expression of PIK3R4 in 80 DLBCL patients, and the survival time of DLBCL patients grouped according to PIK3R4 mRNA expression was compared. Results: PIK3R4 is up-regulated in several malignant tumours, including DLBCL. Bioinformatics analyses revealed that PIK3R4 exhibits prognostic value in DLBCL patients, and the upregulation of this gene in DLBCL samples was subsequently validated. In the functional category, GO analysis revealed that PIK3R4-related genes are enriched in ribosomal RNA metabolic process, the DNA damage response, mitochondrial gene expression, and nucleoside metabolic process. KEGG pathway analysis showed the enrichment of PIK3R4-related genes in the ribosome, oxidative phosphorylation, proteasome, and cellular senescence pathways. More importantly, the expression of PIK3R4 in DLBCL was correlated with the immune cell content in the cancer microenvironment, CD8(+) T-cell and neutrophil infiltration and the levels of several immune checkpoint molecules, including BTN3A2, BTN3A1, PRF1, CXCL9, PDCD1, and TIGIT. Conclusion: Our study demonstrated that PIK3R4, as a novel immune microenvironment-related gene, may represent an important diagnostic, prognostic, or therapeutic biomarker in DLBCL patients.

Improving the Bioactivity and Stability of Embedded Enzymes by Covalent Organic Frameworks.

De novo embedding enzymes within reticular chemistry materials have shown the enhancement of physical and chemical stability for versatile catalytic reactions. Compared to metal-organic frameworks (MOFs), covalent organic frameworks (COFs) are usually considered to be the more superior host of enzymes because of their large channels with low diffusion barriers, outstanding chemical/thermal stability, and metal-free nature. However, detailed investigations on the comparison of COFs and MOFs in enhancing biocatalytic performance have not been explored. Here, we de novo encapsulated enzymes within two COFs via a mechanochemical strategy, which avoided the extreme synthetic conditions of COFs and highly maintained the biological activities of the embedded enzymes. The enzymes@COFs biocomposites exhibited a much higher activity (3.4-14.7 times higher) and enhanced stability than those in MOFs (ZIF-8, ZIF-67, HKUST-1, MIL-53, and CaBDC), and the rate parameter (kcat/Km) of enzyme@COFs was 41.3 times higher than that of enzyme@ZIF-8. Further explorations showed that the conformation of enzymes inside MOFs was disrupted, owing to the harmful interfacial interactions between enzymes and metal ions as confirmed by ATR-FTIR, fluorescence spectroscopy, and XPS data. In contrast, enzymes that were embedded in metal-free COFs highly preserved the natural conformation of free enzymes. This study provides a better understanding of the interfacial interactions between reticular supports and enzymes, which paves a new road for optimizing the bioactivities of immobilized enzymes.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

KLK2 single-nucleotide polymorphism rs198977 is associated with increased susceptibility and hyperleukocytosis in AML.

Introduction: Acute myeloid leukemia (AML) is a heterogeneous myeloid malignancy with abnormal molecular diversity. Tissue kallikrein 2 (KLK2) is a kind of serine protease, and has a close relationship with the occurrence and development of malignant tumors. Single nucleotide polymorphism (SNP) of various genes are associated with susceptibility, treatment and survival of AML. Methods: We investigated the association of KLK2 SNPs rs198977 and rs2664155 with AML. We recruited 284 AML patients and 280 healthy controls from the Han population and genotyping KLK2 SNPs rs198977 and rs2664155 by MassARRAY system. Results: Using clinical data from AML patients and controls, including AML susceptibility, blood count, risk stratification, response to induced chemotherapy and survival, our results showed an increased risk of AML susceptibility with KLK2 rs198977 TT genotype in the recessive model. Regarding white blood cell counts in AML patients, the results showed an increased risk of hyperleukocytosis with the TT genotype of KLK2 rs198977 in a codominant model. Moreover, in the recessive model, AML with KLK2 SNPs rs198977 TT genotype had an increased risk of hyperleukocytosis. No significant correlation was found between KLK2 rs2664155 and AML. Discussion: This study suggests that KLK2 rs198977 may be an important genetic factor in the occurrence of AML and hyperleukocytosis in AML, providing a new perspective for disease progression and new therapeutic targets.

Immune checkpoint-related gene polymorphisms are associated with acute myeloid leukemia.

BACKGROUND: Chemotherapy is still the standard regimen for treating acute myeloid leukemia (AML) and its disappointing efficacy requires the urgent need for new therapeutic targets. It is well known that immune response plays an increasingly significant role in the pathogenesis of AML. METHODS: We detected nine single nucleotide polymorphisms (SNPs) in immune checkpoint-related genes, including PD1, LAG3, TIM3, and TIGIT in 285 AML inpatients and 324 healthy controls. SNP genotyping was performed on the MassARRAY platform. Furthermore, we analyzed the relationship between the susceptibility and prognosis of AML and the selected SNPs. RESULTS: Our results showed that rs2227982 and rs10204525 in PD1 were significantly associated with susceptibility to AML after false discovery rate correction. PD1 rs10204525 also showed a significant correlation with the response to chemotherapy and risk stratification of AML. Importantly, the AA genotype of PD1 (rs2227982) under the recessive model showed a negative impact on AML prognosis independently. CONCLUSIONS: Our results indicate that PD1 SNPs are important for susceptibility and prognosis in AML, which may provide a new therapeutic target for AML patients.

Mitochondrial apoptosis-related gene polymorphisms are associated with responses to anthracycline-based chemotherapy in acute myeloid leukaemia.

Background: Although anthracyclines are the first-line chemotherapy drugs for treating non-M3 acute myeloid leukaemia (AML), their efficacy remains limited. It is important to identify factors that influence the efficacy of anthracyclines against AML. Mitochondrial apoptosis-related genes play significant roles in the pathogenesis, treatment, and prognosis of AML. Methods: We utilized the CRISPR/Cas9 screening system to find AML anthracyclines resistance related genes and several mitochondrial apoptosis-related genes, such as BCL2L11, CASP8, TP63, TP53BP2, PLAUR, SOD2, BNIP3L, and MMP9, were screened out. Then, DNA from 279 patients with AML and 321 healthy individuals were extracted and the contributions of single nucleotide polymorphisms (SNPs) within these genes to the patient's chemotherapy response, susceptibility to AML, and overall survival were investigated. Results: Our findings indicated that SNP rs4251864 in the PLAUR gene was associated with an increase in complete remission after anthracycline-based induction chemotherapy. rs4880 in SOD2 was associated with the response to the second course of chemotherapy, whereas rs3789068 in BCL2L11 was associated with susceptibility to AML. Conclusions: Our results about the association of SNPs in mitochondrial apoptosis-related genes with the response to anthracycline-based chemotherapy in AML provide an important reference for predicting the treatment outcomes in patients with this disease.

EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway.

Aberrant expression of circRNAs has been proven to play a crucial role in the progression of acute myeloid leukemia (AML); however, its regulatory mechanism remains unclear. Herein, we identified a novel circRNA, Circ_0001187, which is downregulated in AML patients, and its low level contributes to a poor prognosis. We further validated their expression in large-scale samples and found that only the expression of Circ_0001187 was significantly decreased in newly diagnosed (ND) AML patients and increased in patients with hematological complete remission (HCR) compared with controls. Knockdown of Circ_0001187 significantly promoted proliferation and inhibited apoptosis of AML cells in vitro and in vivo, whereas overexpression of Circ _0001187 exerted the opposite effects. Interestingly, we found that Circ_0001187 decreases mRNA m6A modification in AML cells by enhancing METTL3 protein degradation. Mechanistically, Circ_0001187 sponges miR-499a-5p to enhance the expression of E3 ubiquitin ligase RNF113A, which mediates METTL3 ubiquitin/proteasome-dependent degradation via K48-linked polyubiquitin chains. Moreover, we found that the low expression of Circ _0001187 is regulated by promoter DNA methylation and histone acetylation. Collectively, our findings highlight the potential clinical implications of Circ _0001187 as a key tumor suppressor in AML via the miR-499a-5p/RNF113A/METTL3 pathway.

Clinical and prognostic profile of SRSF2 and related spliceosome mutations in patients with acute myeloid leukemia.

BACKGROUND: Mutations in splicing factor (SF) genes are frequently detected in myelodysplastic syndrome, but their clinical and prognostic relevance in acute myeloid leukemia (AML) have rarely been reported. METHODS: A total of 368 newly diagnosed non-M3 AML patients were included in this study. Next generation sequencing including four SF genes was performed on the genomicDNA. The clinical features and survival were analyzed using statistical analysis. RESULTS: We found that 64 of 368 patients harbored SF mutations. The SF mutations were much more frequently found in older or male patients. SRSF2 mutations were shown obviously co-existed with IDH2 mutation. The level of measurable residual disease after first chemotherapy was higher in SF-mutated patients compared to that in SF-wild patients, while the complete remission rate was significantly decreased. And the overall survival of SF-mutated patients was shorter than that of SF-wild patients. Moreover, our multivariable analysis suggests that the index of male, Kit mutation or ZRSR2 mutation was the independent risk factor for overall survival. SRSF2mut was associated with older age, higher proportion of peripheral blasts or abnormal cell proportion by flow cytometry. CONCLUSION: SF mutation is a distinct subgroup of AML frequently associated with clinic-biological features and poor outcome. SRSF2mut could be potential targets for novel treatment in AML.