Functions of N6-methyladenosine (m6A) RNA modifications in acute myeloid leukemia.

N6-methyladenosine (m6A) is the most common modification of eukaryotic RNA. m6A participates in RNA splicing, nuclear export, translation, and degradation through regulation by methyltransferases, methylation readers, and demethylases, affecting mRNA stability and translation efficiency. Through the dynamic and reversible regulatory network composed of " Writers-Erasers-Readers", m6A modification plays a unique role in the process of hematopoiesis. Acute myeloid leukemia (AML) is a heterogeneous disease characterized by malignant proliferation of hematopoietic stem cells/progenitor cells. Many studies have shown that m6A-related proteins are abnormally expressed in AML and play an important role in the occurrence and development of AML, acting as carcinogenic or anticancer factors. Here, we describe the mechanisms of action of reversing m6A modification in hematopoiesis and AML occurrence and progression to provide a basis for further research on the role of m6A methylation and its regulatory factors in normal hematopoiesis and AML, to ultimately estimate its potential clinical value.

Shared genetic factors and causal association between chronic hepatitis C infection and diffuse large B cell lymphoma.

BACKGROUND: Epidemiological research and systematic meta-analyses indicate a higher risk of B-cell lymphomas in patients with chronic hepatitis C virus (HCV) compared to non-infected individuals. However, the genetic links between HCV and these lymphomas remain under-researched. METHODS: Mendelian randomization analysis was employed to explore the association between chronic hepatitis C (CHC) and B-cell lymphomas as well as chronic lymphocytic leukemia (CLL). Approximate Bayes Factor (ABF) localization analysis was conducted to find shared genetic variants that might connect CHC with B-cell lymphomas and chronic lymphocytic leukemia (CLL). Furthermore, The Variant Effect Predictor (VEP) was utilized to annotate the functional effects of the identified genetic variants. RESULTS: Mendelian randomization revealed a significant association between CHC and increased diffuse large B cell lymphoma (DLBCL) risk (OR: 1.34; 95% CI: 1.01-1.78; P = 0.0397). Subsequent colocalization analysis pinpointed two noteworthy variants, rs17208853 (chr6:32408583) and rs482759 (chr6:32227240) between these two traits. The annotation of these variants through the VEP revealed their respective associations with the butyrophilin-like protein 2 (BTNL2) and notch receptor 4 (NOTCH4) genes, along with the long non-coding RNA (lncRNA) TSBP1-AS1. CONCLUSION: This research provides a refined genetic understanding of the CHC-DLBCL connection, opening avenues for targeted therapeutic research and intervention.

Molecular mechanisms of ferroptosis and its roles in leukemia.

Cell death is a complex process required to maintain homeostasis and occurs when cells are damage or reach end of life. As research progresses, it is apparent that necrosis and apoptosis do not fully explain the whole phenomenon of cell death. Therefore, new death modalities such as autophagic cell death, and ferroptosis have been proposed. In recent years, ferroptosis, a new type of non-apoptotic cell death characterized by iron-dependent lipid peroxidation and reactive oxygen species (ROS) accumulation, has been receiving increasing attention. Ferroptosis can be involved in the pathological processes of many disorders, such as ischemia-reperfusion injury, nervous system diseases, and blood diseases. However, the specific mechanisms by which ferroptosis participates in the occurrence and development of leukemia still need to be more fully and deeply studied. In this review, we present the research progress on the mechanism of ferroptosis and its role in leukemia, to provide new theoretical basis and strategies for the diagnosis and treatment of clinical hematological diseases.

Causal relationships between circulating inflammatory cytokines and diffuse large B cell lymphoma: a bidirectional Mendelian randomization study.

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Studies indicated that inflammatory cytokines involved in the occurrence and progression of DLBCL and it is challenging to discern causality from the effects due to the presence of feedback loops. We conducted a bidirectional Mendelian randomization (MR) study to investigate the potential causal relationship between DLBCL and inflammatory cytokines. The genetic variants associated with inflammatory cytokines were obtained from a genome-wide association study (GWAS) involving 8293 European participants, and the data on 1010 individuals with DLBCL were sourced from the FinnGen consortium. The primary method employed in this study was the inverse-variance weighted (IVW) method, with supplementary analyses conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. Based on the IVW method, genetically predicted that increasing level of Monokine induced by interferon gamma (MIG/CXC chemokine ligand 9, CXCL9) [OR: 1.31; 95% CI: 1.05-1.62; P = 0.01] and interferon gamma-induced protein 10(IP-10/CXC chemokine ligand 10, CXCL10) [OR: 1.30; 95% CI: 1.02-1.66; P = 0.03] showed suggestive associations with DLBCL risk. DLBCL may increase the level of macrophage colony-stimulating factor (M-CSF) [OR: 1.12; 95% CI: 1.01-1.2; P = 0.03], tumor necrosis factor beta (TNF-ß) [OR: 1.16; 95% CI: 1.02-1.31; P = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR: 1.07; 95% CI: 1.01-1.13; P = 0.02]. This study presents evidence supporting a causal relationship between inflammation cytokines and DLBCL. Specifically, MIG/CXCL9 and IP-10/CXCL10 were identified as indicators of upstream causes of DLBCL; while, DLBCL itself was found to elevate the levels of M-CSF, TNF-ß, and TRAIL. These findings suggest that targeting specific inflammatory factors through regulation and intervention could serve as a potential approach for the treatment and prevention of DLBCL.

Gene Mutations and Targeted Therapies of Myeloid Sarcoma.

OPINION STATEMENT: Myeloid sarcoma, a rare malignant tumor characterized by the invasion of extramedullary tissue by immature myeloid cells, commonly occurs concomitantly with acute myeloid leukemia, myelodysplastic syndromes, or myeloproliferative neoplasms. The rarity of myeloid sarcoma poses challenges for diagnosis and treatment. Currently, treatments for myeloid sarcoma remain controversial and primarily follow protocols for acute myeloid leukemia, such as chemotherapy utilizing multi-agent regimens, in addition to radiation therapy and/or surgery. The advancements in next-generation sequencing technology have led to significant progress in the field of molecular genetics, resulting in the identification of both diagnostic and therapeutic targets. The application of targeted therapeutics, such as FMS-like tyrosine kinase 3(FLT3) inhibitors, isocitrate dehydrogenases(IDH) inhibitors, and the B cell lymphoma 2(BCL2) inhibitors, has facilitated the gradual transformation of traditional chemotherapy into targeted precision therapy for acute myeloid leukemia. However, the field of targeted therapy for myeloid sarcoma is relatively under-investigated and not well-described. In this review, we comprehensively summarize the molecular genetic characteristics of myeloid sarcoma and the current application of targeted therapeutics.

MALAT-1 regulates the AML progression by promoting the m6A modification of ZEB1.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) is abnormally upregulated in various human cancers. However, the role of MALAT-1 in acute myeloid leukemia (AML) remains unclear. This study investigated the expression and function of MALAT-1 in AML. MTT assay was used to determine cell viability, qRT-PCR was applied to determine the RNA levels. Western blot was performed to detect the protein expression. Flow cytometry was conducted to measure cell apoptosis. RNA pull-down assay was carried out to detect the interaction between MALAT-1 and METTL14. RNA FISH assay was performed to determine the localization of MALAT-1 and METTL14 in AML cells. Our results have revealed the key role of MEEL14 and m6A modification in AML. Besides, MALAT-1 was significantly up-regulated in AML patients. MALAT-1 knockdown inhibited the proliferation, migration and invasion of AML cells, and induced cell apoptosis; additionally, MALAT-1 binding to METTL14 promoted the m6A modification of ZEB1. Besides, ZEB1 overexpression partially reversed the effect of MALAT-1 knockdown on the cellular functions of AML cells. Taken together, MALAT-1 promoted the aggressiveness of AML through regulating m6A modification of ZEB1.

Erratum to: MALAT-1 regulates the AML progression by promoting the m6A modification of ZEB1.

Erratum.

Associations between genetic polymorphisms in interleukin-10 and hematological oncology: evidence from a meta-analysis.

Background: Associations between polymorphisms in interleukin-10 (IL-10) and hematological oncology were already explored by many genetic association studies, with controversial findings. The aim of this meta-analysis was to more comprehensively analyze associations between polymorphisms in IL-10 and hematological oncology by combing the results of all relevant studies.Methods: Eligible articles were searched from Pubmed, Embase, WOS and CNKI. The latest literature searching update was performed on 8 October 2019. We used Review Manager to combine the results of eligible studies.Results: Forty-one articles were included in this meta-analysis. IL-10 rs1800890 polymorphism was found to be significantly associated with hematological oncology under AA vs. TT+TA (recessive comparison, OR = 1.12, 95% CI 1.02-1.24), and rs1800896 polymorphism was also found to be significantly associated with hematological oncology under AA vs. AG+GG (dominant comparison, OR = 0.89, 95% CI 0.83-0.95) in overall combined analyses. In subgroup analyses, we observed positive results for rs1800871 (recessive comparison), rs1800872 (dominant, recessive and allele comparisons), and rs1800896 (dominant and allele comparisons) polymorphisms in the non-Hodgkin's lymphoma (NHL) subgroup. Besides, we also detected positive associations between rs1800872 polymorphism and acute leukemia (AL) (dominant and recessive comparisons) and found significant associations between rs1800896 polymorphism and chronic leukemia (CL) (recessive comparison).Conclusion: In summary, this meta-analysis demonstrated that IL-10 rs1800890, rs1800896, rs1800871 and rs1800872 polymorphisms may confer susceptibility to hematology oncology, especially for NHL.

[TF-1 cell apoptosis-inducing effect of matrine and its effect on SALL4 expression].

OBJECTIVE: To explore the mechanism of matrine (Mat) induced human erythroleukemia TF-1 cell apoptosis and its effect on SALL4 expression. METHOD: Different concentrations of the Mat (0.5, 1.0, 1.5, 2.0 g x L(-1) ) were cultured in vitro in TF-1 cells at different time (24, 48, 72 h). Cell proliferation was assayed by MTT. Cell cycle was determined by flow cytometry (FCM). Cell apoptosis was detected by Annexin V and PI double staining method. SALL4 mRNA expression was detected by reverse transcription RT-PCR (RTT-PCR). RESULT: Administrated with Mat (0.5-2.0 g x L(-1)) after 24, 48, 72 h, the proliferation of TF-1 cells were inhibited (P < 0.01) , and in dose- and time-dependent manner. Half inhibitory concentration (IC50 ) was 1.0 g L(-1) at 48 h. After 48 h that the Mat acted on TF-1 cells, the proportion of G0/G1 phase cells increased while compared with the control group, and S phase cells decreased (P < 0.01). Apoptosis were 8.6% , 11.21%, 15.26% , 17.63%, which showed statistically significant difference (P < 0.01) compared with the control group (5.05%). RT-PCR results showed the ratio between SALL4 mRNA expression and beta-actin (internal reference) expression significantly decreased (P < 0.01) with Mat dose increased. CONCLUSION: In a certain range of concentration and time, Mat can inhibit TFT-1 cells proliferation. The mechanism is to make the cells G0/G1 phase blocked, to inhibit SALL4 gene expression and induce cell apoptosis.