Progression To Acute Myeloid Leukemia Research Articles

P110CUX1 promotes acute myeloid leukemia progression via regulating pyridoxal phosphatase expression and activating PI3K/AKT/mTOR signaling pathway.

As an evolutionarily conserved transcription factor, Cut-like homeobox 1 (CUX1) plays crucial roles in embryonic and nervous system development, cell differentiation, and DNA damage repair. One of its major isoforms, p110CUX1, exhibits stable DNA binding capabilities and contributes to the regulation of cell cycle progression, proliferation, migration, and invasion. While p110CUX1 has been implicated in the progression of various malignant tumors, its involvement in acute myeloid leukemia (AML) remains uncertain. This study aims to elucidate the role of p110CUX1 in AML. Our findings reveal heightened expression levels of both p110CUX1 and pyridoxal phosphatase (PDXP) in AML cell lines. Overexpression of p110CUX1 promotes AML cell proliferation while inhibiting apoptosis and differentiation, whereas knockdown of PDXP yields contrasting effects. Mechanistically, p110CUX1 appears to facilitate AML development by upregulating PDXP expression and activating the PI3K/AKT/mTOR signaling pathway. Animal experimental corroborate the pro-AML effect of p110CUX1. These results provide experimental evidence supporting the involvement of the p110CUX1-PDXP-PI3K/AKT/mTOR axis in AML progression. Hence, targeting p110CUX1 may hold promise as a therapeutic strategy for AML.

SRSF12 is a prognostic biomarker involved in immune infiltration in acute myeloid leukemia

ABSTRACT Background Acute myeloid leukemia (AML) is a disease characterized by the proliferation of abnormal cells originating from blood stem cells. Understanding the pathogenesis and progression of AML, as well as identifying molecular markers for early diagnosis and prognosis assessment, is of paramount importance. Methods The AML dataset was obtained from the Cancer Genome Atlas (TCGA), while the normal sample dataset was derived from the Genotype-Tissue Expression(GTEx) dataset. Furthermore, the association between SRSF12 expression and drug response was assessed using the Cancer Therapeutic Response Portal (CTRP) database to evaluate its potential therapeutic value. Finally, SRSF12 expression in AML cells was measured using quantitative real-time PCR (qRT-PCR). Result The difference in SRSF12 expression between 13 types of tumors and normal tissue samples was found to be statistically significant (P < 0.05). SRSF12 exhibited predominantly high expression in AML, indicating its potential as a diagnostic and prognostic marker for AML patients. High expression of SRSF12, along with age and cytogenetic risk, emerged as independent predictors of favorable prognosis in AML patients (P < 0.05). PCR demonstrated a significant increase in SRSF12 expression in AML patients. Conclusion Overall, our findings suggest that the high expression of SRSF12 in AML patients is a poor prognostic factor, which may provide a new option for the diagnosis, and targeted therapy of AML.

Microbial metabolomics in acute myeloid leukemia: From pathogenesis to treatment.

Acute myeloid leukemia (AML), the most common leukemia in adults, is a biologically heterogeneous disease arising from clonally proliferating hematopoietic stem cells. Increased appreciation of novel genetic methods has improved the understanding of AML biology. Recently, the emerging field of metabolomics has indicated qualitative and quantitative alterations in metabolic profiles in AML pathogenesis, progression and treatment. Multiple metabolic and molecular pathways regulate human metabolism and host-microbiome interactions may significantly affect this biochemical machinery. Microbiota have been found to play a significant role in hematopoietic function, metabolism and immunity, contributing to AML occurrence. A large number of studies have highlighted the importance of the composition and diversity of the gut microbiota (GM) in response to treatment and prognosis in AML. Moreover, strong evidence emphasizes the detrimental link between dysbiosis and infectious complications, a leading cause of morbidity and mortality for patients with AML. Several microbiota-related mechanisms have been linked to particular changes in host physiology so far, and microbial-derived metabolites belong to one of the most important. Circulating in the body, they modulate human conditions both locally and systemically. The extensive and diverse repertoire of bacterial metabolic functions plays a critical role in numerous processes, including leukemogenesis. Integrative analysis of microbiome and metabolome data is a promising avenue for better understanding the complex relationship between the microbiota, biochemical alterations and AML pathogenesis to effectively prevent, treat and mitigate its outcomes. This review concentrates on the pathologic roles and therapeutic implications of microbe-derived metabolites in AML settings.

Lenalidomide in Transfusion-Dependent IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes and Isolated Del(5q): Results of a European Postauthorization Safety Surveillance Study

BackgroundThis noninterventional postauthorization safety study assessed the safety and effectiveness of lenalidomide in patients with transfusion-dependent, International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk myelodysplastic syndromes (MDS) associated with isolated deletion of 5q (del[5q]) who were treated in routine care. Patients and MethodsEligible adult patients in the lenalidomide cohort had transfusion-dependent, IPSS Low- or Int-1-risk MDS and isolated del(5q) and had received ≥ 1 dose of lenalidomide between 2014 and 2022. The primary endpoint was the 24-month cumulative incidence of acute myeloid leukemia (AML) progression. Overall survival (OS) was estimated by Kaplan–Meier analysis and safety data were collected. ResultsIn total, 296 patients received ≥ 1 dose of lenalidomide (lenalidomide cohort, safety population) and 277 had received ≥ 1 complete cycle of lenalidomide (primary population). In the safety population, 44.3% of patients completed 3-year follow-up and 55.1% discontinued, with 33.1% discontinuing due to death. In the primary population, 24-month cumulative incidence of AML progression was 12.7% (95% confidence interval, 8.9%-17.1%) and estimated OS probability was 78.3% at 24 months and 63.9% at 36 months. Grade 3/4 treatment-emergent adverse events were experienced by 67.2% of the safety population, and these led to discontinuation in 35.5% of patients. There were no new safety signals. ConclusionThese real-world data support the established benefit-risk profile of lenalidomide in transfusion-dependent IPSS Low- or Int-1-risk MDS with isolated del(5q).

Effective Prevention and Treatment of Acute Leukemias in Mice by Activation of Thermogenic Adipose Tissues.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or β3-adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML- and ALL-bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA-mediated anti-leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA-treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti-leukemic effects and reduces chemotoxicity. These data provide a new TATA-based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies.

Potential Correlation between Gene Mutations and Metabolic Changes in Acute Myeloid Leukemia

Abstract: Acute myeloid leukemia (AML) is a common type of leukemia. However, the understanding of AML remains insufficient. The pathological progression of AML is closely related to chromosome abnormalities and genetic mutations. Gene mutation is an important factor in the pathogenesis of AML and a potential cause of drug resistance. Recent studies have shown that gene mutations in AML can cause metabolic changes. Metabolites, as downstream products of human physiological activities, can amplify physiological and disease-related signals. Therefore, the analysis of metabolite markers related to gene mutations can be used for early prediction of the occurrence of the disease. This review describes the types and significance of AML gene mutations and analyzes the characteristics of metabolic changes related to gene mutations.

Inhibition of TGF-β signaling in bone marrow endothelial cells promotes hematopoietic recovery in acute myeloid leukemia patients

Although it is an effective treatment for acute myeloid leukemia (AML), chemotherapy leads to myelosuppression and poor hematopoietic reconstruction. Hematopoiesis is regulated by bone marrow (BM) endothelial cells (ECs), and BM ECs are dysfunctional in acute leukemia patients with poor hematopoietic reconstitution after allogenic hematopoietic stem cell transplantation. Thus, it is crucial to explore the underlying mechanism of EC impairment and establish strategies for targeted therapy. TGF-β signaling was found to be upregulated in ECs from AML patients in complete remission (CR ECs) and led to CR EC damage. Administration of a TGF-β inhibitor rescued the dysfunction of ECs caused by TGF-β1 expression in vitro, especially their hematopoiesis-supporting ability. Moreover, inhibition of TGF-β expression repaired the BM EC damage triggered by chemotherapy in both AML patients in vitro and in an AML-CR murine model, and restored normal hematopoiesis without promoting AML progression. Mechanistically, our data reveal alterations in the transcriptomic pattern of damaged BM ECs, accompanied by the overexpression of downstream molecules TGF-βRI, pSmad2/3, and functional genes related to adhesion, angiogenesis suppression and pro-apoptosis. Collectively, our findings reveal for the first time that the activation of TGF-β signaling leads to BM EC dysfunction and poor hematopoietic reconstitution. Targeting TGF-β represents a potential therapeutic strategy to promote multilineage hematopoiesis, thereby benefiting more cancer patients who suffer from myelosuppression after chemotherapy.

RPS6KA1 is a histone acetylation-related oncoprotein in acute myeloid leukemia which is targeted by afzelin

BackgroundHistone acetylation plays a critical role in the progression of acute myeloid leukemia (AML). This study aimed to explore the prognostic significance and biological implications of histone acetylation-related genes in AML and to identify potential oncoproteins and therapeutic compounds.MethodsGenes associated with AML and histone acetylation were identified using the TCGA-LAML and IMEx Interactome databases. A histone acetylation-related risk model was developed using the least absolute shrinkage and selection operator method. The prognostic value of the model was evaluated through Kaplan-Meier survival analysis, time-dependent receiver operating characteristic curve, univariate and multivariate Cox regression, and nomogram calibration. Key genes were identified using random forest, support vector machine, and multivariate Cox analysis. Molecular docking was employed to assess the binding affinity between ribosomal protein S6 kinase A1 (RPS6KA1) and potential compounds. Furthermore, the effects of RPS6KA1 and afzelin on the malignant behaviors and downstream pathways of AML cells were validated through in vitro experiments.ResultsA risk model composed of 6 genes, including HDAC6, CREB3, KLF13, GOLGA2, RPS6KA1 and ZMIZ2, was established, demonstrating strong prognostic predictive capability. Among these, RPS6KA1 emerged as a key risk factor linked to histone acetylation status in AML. Elevated RPS6KA1 expression was observed in AML samples and was associated with poor prognosis. RPS6KA1 knockdown suppressed AML cell proliferation, migration, and invasion, induced G0/G1 phase arrest, and promoted apoptosis. Additionally, RPS6KA1 was identified as a potential target for afzelin, which exhibited anti-AML activity by inactivating RPS6KA1.ConclusionHistone acetylation status is closely associated with AML patient prognosis. RPS6KA1 acts as an oncoprotein in AML, facilitating disease progression. Afzelin may represent a novel therapeutic agent for AML by targeting RPS6KA1, which requires validation by clinical trials.

High expression of ARHGEF5 predicts unfavorable prognosis in acute myeloid leukemia

Acute myeloid leukemia (AML) is a highly heterogeneous hematological neoplasm, highlighting the need for new molecular markers to improve prognosis prediction and therapeutic strategies. While Rho guanine nucleotide exchange factor 5 (ARHGEF5) is known to be overexpressed in various cancers, its role in AML is not well understood. This study investigates the correlation between ARHGEF5 expression and AML using data from the Cancer Genome Atlas (TCGA). ARHGEF5 expression levels in AML patients and normal samples were compared using the Wilcoxon rank-sum test. The Kaplan–Meier method and Cox regression analysis (CRA) assessed the association between ARHGEF5 expression and patient survival. A prognostic nomogram was constructed using CRA, incorporating patient age and cytogenetic risk.Our findings indicate significant overexpression of ARHGEF5 in AML compared to normal samples. Elevated ARHGEF5 levels were associated with poor prognosis, particularly in patients ≤ 60 years, those with NPM1 mutations, FLT3 mutation-positive, and wild-type RAS (P < 0.05). CRA confirmed that high ARHGEF5 expression independently predicts poor prognosis. Additionally, 412 differentially expressed genes (DEGs) were identified between high and low ARHGEF5 expression groups, with 216 genes upregulated and 196 downregulated. Pathway enrichment analyses using GO and KEGG, along with protein–protein interaction network and single sample gene set enrichment analyses, revealed key pathways and immune cell associations linked to ARHGEF5. These findings suggest that ARHGEF5 overexpression could serve as a biomarker for unfavorable outcomes in AML, providing insights into the underlying mechanisms of AML onset and progression.

The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.

Oncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and autophagy, two key stem cell proteostasis pathways, to prevent unfolded protein accumulation. Inactivation of HSF1 sensitized human AML cells to proteasome inhibition, marked by unfolded protein accumulation, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival, and significant slowing of disease progression and extension of survival in vivo . Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed AML cells, and significantly reduced AML burden and extended survival in vivo . Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, without severely affecting normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition also activated the integrated stress response, but surprisingly this occurred in a PKR-dependent manner. These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.

Clonal Evolution in 207 Cases of Refractory or Relapsed Acute Myeloid Leukemia.

Clonal evolution (CE) is a driving force behind the development and progression of acute myeloid leukemia (AML). Advances in molecular and cytogenetic assays have improved the depth and breadth of detection of CE in AML, which is defined here as a detected change in cytogenetic or molecular profile at relapsed or refractory (RR) disease. In this study, we demonstrate the clinical impact of CE in a cohort of patients with RR AML treated between 2013 and 2023. We discovered CE is significantly more frequent in relapsed disease (58.2%, [46.6%, 69.2%]) than in refractory disease (21.1%, [14.4%, 29.2%], p < 0.001). CE negatively impacts prognosis when detected by conventional karyotyping in refractory disease (4.2 vs. 13.9 months, p < 0.011). In contrast with prior literature, CE had no impact on overall survival if detected in relapsed disease. Surprisingly, those who achieved negative measurable residual disease (MRD) were no more likely to eliminate their original clone than those who did not (p = 1). We found several cytogenetic and molecular signatures which may predispose to CE: aberrations of chromosome 17, trisomy 8, TP53, KRAS, and FLT3-TKD. Finally, physicians were less likely to retreat those with CE with IC after receiving IC as first-line therapy (35.0% vs. 70.9%, p = 0.004). This study illustrates the role of CE in chemotherapy-resistant AML; we identify unique cytogenetic and molecular signatures that define a subset of patients associated with a dismal prognosis. As next-generation sequencing panels expand and new methods to characterize cytogenetic abnormalities emerge, our findings establish a basis for future studies investigating the prognostic and therapeutic impact of CE.

Identification of immunity- and ferroptosis-related signature genes as potential design targets for mRNA vaccines in AML patients.

Immune-associated ferroptosis plays an important role in the progression of acute myeloid leukemia (AML); however, the targets that play key roles in this process are currently unknown. This limits the development of mRNA vaccines based on immune-associated ferroptosis for clinical therapeutic applications. In this study, based on the rich data resources of the TCGA-LAML cohort, we analyzed the tumor mutational burden (TMB), gene mutation status, and associations between immune and ferroptosis genes to reveal the disease characteristics of AML patients. To gain a deeper understanding of differentially expressed genes, we applied the Limma package for differential expression analysis and integrated data sources such as ImmPort Shared Data and FerrDb V2. Moreover, we established gene modules related to TMB according to weighted gene coexpression network analysis (WGCNA) and explored the functions of these modules in AML and their relationships with TMB. We focused on the top 30 most frequent genes through a detailed survey of missense mutations and single nucleotide polymorphisms (SNPs) and selected potentially critical gene targets for subsequent analysis. Based on the expression of these genes, we successfully subgrouped AML patients and found that the subgroups associated with TMB (C1 and C2) exhibited significant differences in survival. The differences in the tumor microenvironment and immune cells between C1 and C2 patients were investigated with the ESTIMATE and MCP-counter algorithms. A predictive model of TMB-related genes (TMBRGs) was constructed, and the validity of the model was demonstrated by categorizing patients into high-risk and low-risk groups. The differences in survival between the high-risk patients and high-TMB patients were further investigated, and potential vaccine targets were identified via immune cell-level analysis. The identification of immunity- and ferroptosis-associated signature genes is an independent predictor of survival in AML patients and provides new information on immunotherapy for AML.

Establishment and verification of a TME prognosis scoring model based on the acute myeloid leukemia single-cell transcriptome

The tumor microenvironment (TME) plays an important role in the occurrence and progression of Acute Myeloid Leukemia (AML). Single-cell sequencing has enabled researchers to explore the correlation between TME subgroups and tumor prognosis, distinguish the existence of drug-resistant subgroups of tumor cells, and unravel the complexity of the AML cellular heterogeneity. We used bone marrow immune cell enrichment analysis from public databases to screen prognostic genes, construct prognostic models, and validate their prognostic significance on independent external datasets and patient samples. A total of 18,251 single cells were obtained to establish prognostic scoring models for 10 key genes including CCL5, ETLS2, and IL2RA.The AML cases were divided into two groups: high-risk and low-risk. The low-risk group exhibited a higher survival rate than the high-risk group. The areas under curves (AUC) of 1-, 3- and 5-year survival curves in the TCGA and GEO training sets were greater than 0.8 and 0.6, respectively, indicating effective prediction. The model’s prognostic efficacy was confirmed across multiple validation sets. It demonstrated increased expression of ETS2, CCL5, and IL2RA in AML samples compared to controls, which was associated with decreased overall survival (OS). This prognostic scoring model based on tumor immune infiltration provides a reference for developing novel treatment strategies for recurrent/refractory AML.

Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties

The leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient-derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential, repopulation capacity, sensitivity to chemotherapy and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for investigating the LSC compartment and designing combinatorial therapeutic strategies in AML.

The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression.

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial-mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments.

PTBP1 is a potential indicator of disease progression in acute myeloid leukemia.

This study aimed to verify a novel potential indicator of disease progression in acute myeloid leukemia (AML) patients. Bone marrow samples were collected from 27 AML patients and 27 controls without hematological malignancies. Polypyrimidine tract-binding protein 1 (PTBP1) expression in bone marrow samples was measured, and the association of PTBP1 with the French-American-British (FAB) classification, cytogenetics, risk stratification, and complete remission (CR) rate was analyzed. The correlation between PTBP1 and Ki-67/p53 expression in AML patients was ultimately evaluated. The results showed that PTBP1 mRNA and protein levels were greater in AML patients than in controls. PTBP1 expression was able to distinguish between AML patients and controls (area under the curve, 0.8601; 95% confidence interval, 0.7632-0.9570). Furthermore, PTBP1 expression was associated with an increased frequency of internal tandem duplication mutations within FMS-like tyrosine kinase-3 (FLT3) and a complex karyotype, while PTBP1 expression was not correlated with FAB classification, monosomal karyotype, isolated biallelic CCAAT/enhancer-binding protein α (CEBPA) mutation, or nucleophosmin 1 (NPM1) mutation in patients with AML. Moreover, PTBP1 expression was associated with a poorer prognosis according to risk stratification and a lower CR rate in AML patients. In addition, PTBP1 expression was positively correlated with the expression of the proliferation marker Ki-67 and negatively correlated with the expression of the apoptosis marker p53 in AML patients. Overall, PTBP1 is a viable biomarker that contributes to the risk prediction and the determination of potential drug targets for AML.

MiR-149-3p Enhances Drug Sensitivity of AML Cells by Inhibiting Warburg Effect Through PI3K/AKT Pathway.

Acute myeloid leukemia (AML) is a kind of heterogeneous hematologic malignancy with high incidence, which is usually treated by intensive and maintenance treatment with large dose of conventional chemotherapy drugs. However, cell resistance is still an unsolved problem. The abnormal expression of miRNAs is closely related to the pathogenesis and progression of AML, and affects the drug resistance of cancer cells. miR-149-3p plays an important role in the resistance of cancer cells to cisplatin, and plays an excellent anti-tumor activity. By studying the function of miR-149-3p, it is expected to find new therapeutic methods to reverse chemotherapy resistance. In order to explore the mechanism of action of miR-149-3p on AML chemotherapeutic drug sensitivity, we explored the relationship between the Warburg effect and AML chemotherapeutic drug resistance. Based on AML cells, transfection of miR-149-3p inhibitor/NC and Warburg effect inhibitor (2DG) and PI3K/AKT pathway inhibitor (LY294002) were used to investigate the mechanism of IFN-γ regulating chemotherapy resistance of AML cells through Warburg effect. Down-regulation of miR-149-3p significantly inhibited drug sensitivity of AML cells. Down-regulation of miR-149-3p significantly promoted proliferation and invasion of AML cells while inhibiting apoptosis by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax. Down-regulation of miR-149-3p significantly promoted the expression of Warburg effect-related proteins hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and Glucose transporter 1 (GLUT1), glucose consumption, lactic acid, and intracellular ATP production. After inhibiting the Warburg effect with 2DG, the effect of miR-149-3p was inhibited, suggesting that upregulation of miR-149-3p reversed AML cell resistance by inhibiting the Warburg effect. In addition, miR-149-3p interacted with AKT1. Down-regulation of miR-149-3p increased the expression of inosine phosphate 3 kinase (PI3K), protein kinase B (AKT), and multi-drug resistance protein (MDR1). LY294002 inhibited the expression of these proteins, and down-regulation of miR-149-3p reversed the effect of LY294002 and improved the drug resistance of cells. Upregulation of miR-149-3p expression may potentially be a therapeutic target for AML resistance. It has been shown to inhibit PI3K/AKT pathway activation, thereby inhibiting the Warburg effect, and affecting cell proliferation, apoptosis, and drug resistance.

A Comparative Analysis of the Immunoglobulin Repertoire in Leukemia Cells and B Cells in Chinese Acute Myeloid Leukemia by High-Throughput Sequencing.

It is common knowledge that immunoglobulin (Ig) is produced by B lymphocytes and mainly functions as an antibody. However, it has been shown recently that myeloblasts from acute myeloid leukemia (AML) could also express Ig and that AML-Ig played a role in leukemogenesis and AML progression. The difference between Ig from myeloblasts and B cells has not been explored. Studying the characteristics of the Ig repertoire in myeloblasts and B cells will be helpful to understand the function and significance of AML-Ig. We performed 5' RACE-related PCR coupled with PacBio sequencing to analyze the Ig repertoire in myeloblasts and B cells from Chinese AML patients. Myeloblasts expressed all five classes of IgH, especially Igγ, with a high expression frequency. Compared with B-Ig in the same patient, AML-Ig showed different biased V(D)J usages and mutation patterns. In addition, the CDR3 length distribution of AML-Ig was significantly different from those of B-Ig. More importantly, mutations of AML-IgH, especially Igμ, Igα, and Igδ, were different from that of B-IgH in each AML patient, and the mutations frequently occurred at the sites of post-translational modification. AML-Ig has distinct characteristics of variable regions and mutations, which may have implications for disease monitoring and personalized therapy.

Remodeling of the bone marrow microenvironment during acute myeloid leukemia progression.

Hematopoiesis requires a complex interplay between the hematopoietic stem and progenitor cells and the cells of the bone marrow microenvironment (BMM). The BMM is heterogeneous, with different regions having distinct cellular, molecular, and metabolic composition and function. Studies have shown that this niche is disrupted in patients with acute myeloid leukemia (AML), which plays a crucial role in disease progression. This review provides a comprehensive overview of the components of vascular and endosteal niches and the molecular mechanisms by which they regulate normal hematopoiesis. We also discuss how these niches are modified in the context of AML, into a disease-promoting niche and how the modified niches in turn regulate AML blast survival and proliferation. We focus on mechanisms of modifications in structural and cellular components of the bone marrow (BM) niche by the AML cells and its impact on leukemic progression and patient outcome. Finally, we also discuss mechanisms by which the altered BM niche protects AML blasts from treatment agents, thereby causing therapy resistance in AML patients. We also summarize ongoing clinical trials that target various BM niche components in the treatment of AML patients. Hence, the BM niche represents a promising target to treat AML and promote normal hematopoiesis.

Significance of targeting DNMT3A mutations in AML.

Acute myeloid leukemia (AML) is the most prevalent form of leukemia among adults, characterized by aggressive behavior and significant genetic diversity. Despite decades of reliance on conventional chemotherapy as the mainstay treatment, patients often struggle with achieving remission, experience rapid relapses, and have limited survival prospects. While intensified induction chemotherapy and allogeneic stem cell transplantation have enhanced patient outcomes, these benefits are largely confined to younger AML patients capable of tolerating intensive treatments. DNMT3A, a crucial enzyme responsible for establishing de novo DNA methylation, plays a pivotal role in maintaining the delicate balance between hematopoietic stem cell differentiation and self-renewal, thereby influencing gene expression programs through epigenetic regulation. DNMT3A mutations are the most frequently observed genetic abnormalities in AML, predominantly in older patients, occurring in approximately 20-30% of adult AML cases and over 30% of AML with a normal karyotype. Consequently, the molecular underpinnings and potential therapeutic targets of DNMT3A mutations in AML are currently being thoroughly investigated. This article provides a comprehensive summary and the latest insights into the structure and function of DNMT3A, examines the impact of DNMT3A mutations on the progression and prognosis of AML, and explores potential therapeutic approaches for AML patients harboring DNMT3A mutations.