Pathogenesis Of Acute Myeloid Leukemia Research Articles

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.

Correlation of SNHG7 and BGL3 expression in patients with de novo acute myeloid leukemia; novel insights into lncRNA effect in PI3K signaling context in AML pathogenesis

BackgroundAcute myeloid leukemia (AML) has been identified as a top priority for discovering a reliable biomarker for treatment improvement and patient outcome prediction due to the heterogeneous nature of AML and the obstacle to find an appropriate treatment strategy for this malignancy. Considering the involvement of long noncoding RNA (lncRNA) SNHG7 and BGL3 found in various cancers, the exact expression pattern of these lncRNAs and their clinical implications in acute myeloid leukemia (AML) continue to be elusive. In order to demonstrate a possible mechanism underlying AML pathogenesis, our goal was to examine BGL3 and SNHG7 lncRNA expressions in PI3K pathway. MethodsThis case-control cross-sectional study were conducted on RNA extracted from blood samples of 30 patients diagnosed with AML (Ayatollah-Khansari hospital, Arak, Iran) and 30 (age and gender matched) healthy controls. The expression levels of SNHG7 and BGL3 lncRNAs and their target genes Akt and PTEN, were measured using qRT-PCR. Subsequently, by means of statistical analysis, we determined the plausible correlation between the expressions of the aforementioned genes and lncRNA respectively. ResultsIn AML samples, a considerable increase in the expression levels of SNHG7 lncRNA and Akr gene was accompanied by a marked reduction in the expression levels of BGL3 lncRNA and PTEN gene. Nevertheless, No significant relationship between the expression level of the indicated genes/lncRNAs and age and sex was found. The remarkable correlation between the expression of genes/lncRNAs and the blast percentage in patients was the notable point in the result of this study. ConclusionsAs the most straightforward interpretation of our results, we propose that perhaps the association between SNHG7 and BGL3 built through the interaction between Akt and PTEN may play a crucial role in the AML pathogenesis and any element of this axis could be a potential novel target for further profound treatment strategies. Nonetheless, in the context of Hematological Malignancies, particularly AML, more detailed studies are needed in this area to elucidate the precise role played by this interesting testis-specific pathway.

Cohesin RAD21 Gene Promoter Methylation in Patients with Acute Myeloid Leukemia.

Aberrant gene promoter methylation is one of the hallmarks of Acute Myeloid Leukemia (AML). RAD21 is an important gene, implicated in sister chromatids cohesion, DNA repair, the regulation of gene transcription, apoptosis and hematopoiesis. In this study, we investigate the possible implication of RAD21 promoter methylation in AML pathogenesis using a cohort of AML patients and a cohort of healthy individuals. RAD21 promoter methylation was found in 24% of patients and in none of the controls (p = 0.023), indicating a possible contribution to AML development. Interestingly, a statistically higher frequency of RAD21 methylation was observed in patients with trisomy 8 (9/21, 42.9%, p = 0.021), while none of the patients with aberrations of chromosome 11 had RAD21 gene promoter methylation (0%, 0/11, p = 0.048). Patients with monosomal and complex karyotypes showed low frequencies of RAD21 methylation (7.7% and 15.4%, respectively) without reaching statistical significance. Moreover, ASXL1 mutations were not found to be associated with RAD21 methylation. This is the first study which provides evidence for a possible pathogenetic role of RAD21 promoter methylation in AML development and especially in AML with trisomy 8. Further studies of RAD21 promoter methylation in large series of different AML genetic subgroups may contribute to the elucidation of AML pathogenesis and to the identification of new epigenetic biomarkers with diagnostic and prognostic value.

Advancements in genetic analysis: Insights from a case study and review of next-generation sequencing techniques for veterinary oncology applications.

Acute myeloid leukemia (AML) poses significant challenges in veterinary medicine, with limited treatment options and poor survival rates. While substantial progress has been made in characterizing human AML, translating these advancements to veterinary practice has been hindered by limited molecular understanding and diagnostic tools. The case study presented illustrates the application of whole genome sequencing in diagnosing AML in a dog, showcasing its potential in veterinary oncology. Our approach facilitated comprehensive genomic analysis, identifying mutations in genes that may be associated with AML pathogenesis in dogs, such as KRAS, IKZF1, and RUNX1. However, without supportive evidence of its clinical utility (eg, association with response to treatment or prognosis), the information is limited to exploration. This article reviews the comparative features of canine AML with human AML and discusses strategies to shrink the knowledge gap between human and veterinary medicine with cost-effective next-generation sequencing (NGS) techniques. By utilizing these approaches, the unique and shared molecular features with human AML can be identified, aiding in molecular classification and therapeutic development for both species. Despite the promise of NGS, challenges exist in implementing it into routine veterinary diagnostics. Cost considerations, turnaround times, and the need for robust bioinformatics pipelines and quality control measures must be addressed. Most importantly, analytical and clinical validation processes are essential to ensure the reliability and clinical utility of NGS-based assays. Overall, integrating NGS technologies into veterinary oncology holds great potential for advancing our understanding of AML and improving disease stratification, in hopes of improving clinical outcomes.

Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.

Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3' UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.

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.

Epigenetic modifications in hematopoietic ecosystem: a key tuner from homeostasis to acute myeloid leukemia.

Hematopoietic stem cells (HSCs) maintain homeostasis in the hematopoietic ecosystem, which is tightly regulated at multiple layers. Acute myeloid leukemia (AML) is a severe hematologic malignancy driven by genetic and epigenetic changes that lead to the transformation of leukemia stem cells (LSCs). Since somatic mutations in DNA methylation-related genes frequently occur in AML, DNA methylation is widely altered and functions as a starting engine for initiating AML. Additionally, RNA modifications, especially N6-methyladenosine (m6A), also play an important role in the generation and maintenance of the hematopoietic ecosystem, and AML development requires reprogramming of m6A modifications to facilitate cells with hallmarks of cancer. Given the complex pathogenesis and poor prognosis of AML, it is important to fully understand its pathogenesis. Here, we mainly focus on DNA methylation and RNA m6A modification in hematopoiesis and AML and summarize recent advances in this field.

Targeting Molecular Signaling Pathways and Cytokine Responses to Modulate c-MYC in Acute Myeloid Leukemia.

Overexpression of the MYC oncogene, encoding c-MYC protein, contributes to the pathogenesis and drug resistance of acute myeloid leukemia (AML) and many other hematopoietic malignancies. Although standard chemotherapy has predominated in AML therapy over the past five decades, the clinical outcomes and patient response to treatment remain suboptimal. Deeper insight into the molecular basis of this disease should facilitate the development of novel therapeutics targeting specific molecules and pathways that are dysregulated in AML, including fms-like tyrosine kinase 3 (FLT3) gene mutation and cluster of differentiation 33 (CD33) protein expression. Elevated expression of c-MYC is one of the molecular features of AML that determines the clinical prognosis in patients. Increased expression of c-MYC is also one of the cytogenetic characteristics of drug resistance in AML. However, direct targeting of c-MYC has been challenging due to its lack of binding sites for small molecules. In this review, we focused on the mechanisms involving the bromodomain and extra-terminal (BET) and cyclin-dependent kinase 9 (CDK9) proteins, phosphoinositide-Akt-mammalian target of rapamycin (PI3K/AKT/mTOR) and Janus kinase-signal transduction and activation of transcription (JAK/STAT) pathways, as well as various inflammatory cytokines, as an indirect means of regulating MYC overexpression in AML. Furthermore, we highlight Food and Drug Administration (FDA)-approved drugs for AML, and the results of preclinical and clinical studies on novel agents that have been or are currently being tested for efficacy and tolerability in AML therapy. Overall, this review summarizes our current knowledge of the molecular processes that promote leukemogenesis, as well as the various agents that intervene in specific pathways and directly or indirectly modulate c-MYC to disrupt AML pathogenesis and drug resistance.

C-FLIP and microRNA 708-5p gene expression in newly diagnosed and chemotherapy in acute myeloid leukemia of Iraqi patient

Abstract: BACKGROUND: C-FLICE-like inhibitory protein (c-FLIP) is a protein that does not merely block apoptosis signaling but also adjusts further pathways of cell death. Acute myeloid leukemia (AML), a nonhomogeneous hematologic malignancy, is the highly common form of AML among adults and is described through the clonal enlargement of myeloid blasts in the bone marrow (BM), peripheral blood, and/or else tissues. OBJECTIVES: The aims of this study were to investigate the role of c-FLIP and microRNA (miRNA) 708-5p as a prospective prognostic biomarker as well as the therapeutic goal in AML. PATIENTS MATERIALS AND METHODS: This study includes two groups of patients (40) individuals newly diagnosed AML patients, (20) AML taking chemotherapy, and (50) apparently healthy volunteers. The study was conducted at the National Center of Hematology/Mustansiriyah University. The methods employed in the analysis include total RNA extraction, complementary cDNA synthesis, and quantitative real-time polymerase chain reaction (PCR) were used to evaluate the gene expression of cFLIP and miRNA-708-5p. Complete blood count to estimate some hematological parameters. RESULTS: The expression of c-FLIP was notably higher in both newly diagnosed and patients under chemotherapy compared to controls with fold expression (3.291 and 2.92), respectively, with a highly significant (P = 0.0001). The increase in miRNA 708-5p expression in newly diagnosed patients with fold expression (5.345), whereas downregulation in patients under chemotherapy with fold expression (0.789) indicates that treatment may restore its levels, contributing to the suppression of c-FLIP and promoting apoptosis. CONCLUSION: The c-FLIP and miRNA708-5p gene might be used as a biological marker for the AML initial diagnosis. The researches emphasize the role of miRNA 708-5p as a tumor suppressor, which negatively regulates the antiapoptotic protein c-FLIP, indicating its potential as a therapeutic target in AML treatment. By modulating the levels of miRNA708-5p, it may be possible to regulate the expression of c-FLIP, thus enhancing the effectiveness of apoptosis-inducing therapies. This suggests the promising development of miRNA-based therapies as part of AML treatment strategies. Furthermore, miRNA 708-5p can act as a prognostic indicator in AML, with its expression levels offering valuable insights into disease progression and patient response to treatment. Further research into miRNA 708-5p can lead to a better understanding of its role in AML pathogenesis and its potential applications in clinical practice.

Comparison of disease and risk classifications of AML before and after incorporation of NGS analysis of bone marrow samples.

Mutation profiling by next-generation sequencing (NGS) has facilitated understanding of the molecular pathogenesis of acute myeloid leukemia (AML), and has been incorporated into the new disease classification (International Consensus Classification; ICC) and risk classification (European LeukemiaNet [ELN] 2022; ELN2022). We compared disease subtypes between the previous disease classification (4th edition of the WHO classification; WHO-4) and the ICC in 91 patients with AML diagnosed at our institution. We also compared disease risk classifications using the previous risk classification (ELN2017) and the ELN2022. Targeted sequencing of bone marrow samples was conducted at Kyoto University. We found that entities under AML with recurrent genetic abnormalities were well-established, with almost no change from the WHO-4 to the ICC. In contrast, 16.7% of cases of AML, not otherwise specified in the WHO-4 were reclassified into AML with mutated TP53, and 36.7% were reclassified into AML with myelodysplasia-related gene mutations or cytogenetic abnormalities per the ICC. Meanwhile, the ELN2017 and ELN2022 showed no difference in concordance indexes in multivariate Cox regression analysis for progression-free and overall survival. The superiority of the ELN2022 over the ELN2017 could not be confirmed in our single-center retrospective study, and further investigation including multicenter prospective studies is needed.

Understanding MDS stem cells: Advances and limitations

In work spanning several decades, extensive studies have focused on the properties of malignant stem cells that drive the pathogenesis of acute myeloid leukemia (AML). However, relatively little attention has been devoted to several serious myeloid malignancies that occur prior to the onset of frank leukemia, including myelodysplastic syndrome (MDS). Like leukemia, MDS is hypothesized to arise from a pool of immature malignant stem and progenitor cells (MDS-SCs) that serve as a reservoir for disease evolution and progression1. While multiple studies have sought to identify and characterize the biology and vulnerabilities of MDS-SCs, yet translation of scientific concepts to therapeutically impactful regimens has been limited. Here, we evaluate the currently known properties of MDS-SCs as well as the post-transcriptional mechanisms that drive MDS pathogenesis at a stem and progenitor level. We highlight limits and gaps in our characterization and understanding of MDS-SCs and address the extent to which the properties of MDS-SC are (and can be) inferred from the characterization of LSCs.

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.

Molecular pathophysiology of germline mutations in acute myeloid leukemia.

Germline (GL) predisposition to acute myeloid leukemia (AML) has been established as an independent disease entity in the latest World Health Organization classification. Following the American College of Medical Genetics and Genomics guidelines, GL variants were interpreted as causal if they were classified as "pathogenic." GL predisposition can be divided into three groups with different phenotypes, and play an important role in the pathogenesis of adult-onset AML. The clinical course and age of onset of myeloid neoplasms varied considerably for each gene. For example, patients with GATA2 GL variants develop AML before the age of 30 along with bone marrow failure, whereas those with DDX41 GL variants tend to develop AML after the age of 50 without any preceding hematological abnormalities or organ dysfunction. A comprehensive analysis of adult-onset myelodysplastic syndromes in transplant donors showed a 7% frequency of pathogenic GL variants, with DDX41 being the most frequent gene mutation at approximately 3.8%. Future research on GL predisposition at any age of myeloid neoplasm onset will assist in early and accurate diagnosis, development of effective treatment strategies, and selection of suitable donors for stem cell transplantation.

6-Gingerol modulates miRNAs and PODXL gene expression via methyltransferase enzymes in NB4 cells: an in silico and in vitro study

This investigation delves into the influence of predicted microRNAs on DNA methyltransferases (DNMTs) and the PODXL gene within the NB4 cell line, aiming to elucidate their roles in the pathogenesis of acute myeloid leukemia (AML). A comprehensive methodological framework was adopted to explore the therapeutic implications of 6-gingerol on DNMTs. This encompassed a suite of bioinformatics tools for protein structure prediction, docking, molecular dynamics, and ADMET profiling, alongside empirical assessments of miRNA and PODXL expression levels. Such a multifaceted strategy facilitated an in-depth understanding of 6-gingerol’s potential efficacy in DNMT modulation. The findings indicate a nuanced interplay where 6-gingerol administration modulated miRNA expression levels, decreasing in DNMT1 and DNMT3A expression in NB4 cells. This alteration indirectly influenced PODXL expression, contributing to the manifestation of oncogenic phenotypes. The overexpression of DNMT1 and DNMT3A in NB4 cells may contribute to AML, which appears modulable via microRNAs such as miR-193a and miR-200c. Post-treatment with 6-gingerol, DNMT1 and DNMT3A expression alterations were observed, culminating in the upregulation of miR-193a and miR-200c. This cascade effect led to the dysregulation of tumor suppressor genes in cancer cells, including downregulation of PODXL, and the emergence of cancerous traits. These insights underscore the therapeutic promise of 6-gingerol in targeting DNMTs and microRNAs within the AML context.

Genomic mutation patterns and prognostic value in de novo and secondary acute myeloid leukemia: A multicenter study from China.

Acute myeloid leukemia (AML) can manifest as de novo AML (dn-AML) or secondary AML (s-AML), with s-AML being associated with inferior survival and distinct genomic characteristics. The underlying reasons for this disparity remain to be elucidated. In this multicenter study, next-generation sequencing (NGS) was employed to investigate the mutational landscape of AML in 721 patients from June 2020 to May 2023.Genetic mutations were observed in 93.34% of the individuals, with complex variations (more than three gene mutations) present in 63.10% of them. TET2, ASXL1, DNMT3A, TP53 and SRSF2 mutations showed a higher prevalence among older individuals, whereas WT1 and KIT mutations were more commonly observed in younger patients. BCOR, BCORL1, ZRSR2, ASXL1 and SRSF2 exhibited higher mutation frequencies in males. Additionally, ASXL1, NRAS, PPMID, SRSF2, TP53 and U2AF1 mutations were more common in patients with s-AML, which PPM1D was more frequently associated with therapy-related AML (t-AML). Advanced age and hyperleukocytosis independently served as adverse prognostic factors for both types of AML; however, s-AML patients demonstrated a greater number of monogenic adverse prognostic factors compared to dn-AML cases (ASXL1, PPM1D, TP53 and U2AF1 in s-AML vs. FLT3, TP53 and U2AF1 in dn-AML). Age and sex-related gene mutations suggest epigenetic changes may be key in AML pathogenesis. The worse prognosis of s-AML compared to dn-AML could be due to the older age of s-AML patients and more poor-prognosis gene mutations. These findings could improve AML diagnosis and treatment by identifying potential therapeutic targets and risk stratification biomarkers.

Machine learning-based biomarker screening for acute myeloid leukemia prognosis and therapy from diverse cell-death patterns

Acute myeloid leukemia (AML) exhibits pronounced heterogeneity and chemotherapy resistance. Aberrant programmed cell death (PCD) implicated in AML pathogenesis suggests PCD-related signatures could serve as biomarkers to predict clinical outcomes and drug response. We utilized 13 PCD pathways, including apoptosis, pyroptosis, ferroptosis, autophagy, necroptosis, cuproptosis, parthanatos, entotic cell death, netotic cell death, lysosome-dependent cell death, alkaliptosis, oxeiptosis, and disulfidptosis to develop predictive models based on 73 machine learning combinations from 10 algorithms. Bulk RNA-sequencing, single-cell RNA-sequencing transcriptomic data, and matched clinicopathological information were obtained from the TCGA-AML, Tyner, and GSE37642-GPL96 cohorts. These datasets were leveraged to construct and validate the models. Additionally, in vitro experiments were conducted to substantiate the bioinformatics findings. The machine learning approach established a 6-gene pan-programmed cell death-related genes index (PPCDI) signature. Validation in two external cohorts showed high PPCDI associated with worse prognosis in AML patients. Incorporating PPCDI with clinical variables, we constructed several robust prognostic nomograms that accurately predicted prognosis of AML patients. Multi-omics analysis integrating bulk and single-cell transcriptomics revealed correlations between PPCDI and immunological features, delineating the immune microenvironment landscape in AML. Patients with high PPCDI exhibited resistance to conventional chemotherapy like doxorubicin but retained sensitivity to dasatinib and methotrexate (FDA-approved drugs for other leukemias), suggesting the potential of PPCDI to guide personalized therapy selection in AML. In summary, we developed a novel PPCDI model through comprehensive analysis of diverse programmed cell death pathways. This PPCDI signature demonstrates great potential in predicting clinical prognosis and drug sensitivity phenotypes in AML patients.

RNA binding protein-directed control of leukemic stem cell evolution and function.

Strict control over hematopoietic stem cell decision making is essential for healthy life-long blood production and underpins the origins of hematopoietic diseases. Acute myeloid leukemia (AML) in particular is a devastating hematopoietic malignancy that arises from the clonal evolution of disease-initiating primitive cells which acquire compounding genetic changes over time and culminate in the generation of leukemic stem cells (LSCs). Understanding the molecular underpinnings of these driver cells throughout their development will be instrumental in the interception of leukemia, the enabling of effective treatment of pre-leukemic conditions, as well as the development of strategies to target frank AML disease. To this point, a number of precancerous myeloid disorders and age-related alterations are proving as instructive models to gain insights into the initiation of LSCs. Here, we explore this myeloid dysregulation at the level of post-transcriptional control, where RNA-binding proteins (RBPs) function as core effectors. Through regulating the interplay of a myriad of RNA metabolic processes, RBPs orchestrate transcript fates to govern gene expression in health and disease. We describe the expanding appreciation of the role of RBPs and their post-transcriptional networks in sustaining healthy hematopoiesis and their dysregulation in the pathogenesis of clonal myeloid disorders and AML, with a particular emphasis on findings described in human stem cells. Lastly, we discuss key breakthroughs that highlight RBPs and post-transcriptional control as actionable targets for precision therapy of AML.

Targeting ferritinophagy impairs quiescent cancer stem cells in acute myeloid leukemia in vitro and in vivo models.

Acute myeloid leukemia (AML) remains a challenging hematological malignancy with poor prognosis and limited treatment options. Leukemic stem cells (LSCs) contribute to therapeutic failure, relapse, and adverse outcome. This study investigates the role of quiescence and related molecular mechanisms in AML pathogenesis and LSC functions to identify potential therapeutic targets. Transcriptomic analysis revealed that the LSC-enriched quiescent cell population has a distinct gene signature with prognostic relevance in patients with AML. Mechanistically, quiescent blasts exhibit increased autophagic activity, which contributes to their sustained viability. Proteomic profiling uncovered differential requirements for iron metabolism between quiescent and cycling cells, revealing a unique dependence of quiescent cells on ferritinophagy, a selective form of autophagy mediated by nuclear receptor coactivator 4 (NCOA4), which regulates iron bioavailability. We evaluated the therapeutic potential of inhibiting NCOA4-mediated ferritinophagy using genetic knockdown and chemical inhibition approaches. In vitro assays showed that suppression of NCOA4 was toxic to leukemic blasts, particularly the CD34+CD38- LSC-enriched population, without affecting normal CD34+ hematopoietic progenitors. In vivo studies using murine patient-derived xenograft (PDX) models of AML confirmed that NCOA4 inhibition reduced tumor burden and impaired LSC viability and self-renewal, indicating a specific vulnerability of these cells to ferritinophagy disruption. Our findings underscore the role of NCOA4-mediated ferritinophagy in maintaining LSC quiescence and function and suggest that targeting this pathway may be an effective therapeutic strategy for AML. This study highlights the potential of NCOA4 inhibition to improve AML outcomes and paves the way for future research and clinical development.

Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects.

Despite the better understanding of the molecular mechanisms contributing to the pathogenesis of acute myeloid leukemia (AML) and improved patient survival in recent years, AML therapy still remains a clinical challenge. For this reason, it is important to search for new therapies that will enable the achievement of remission. Recently, the Food and Drug Administration approved three mutant IDH (mIDH) inhibitors for the treatment of AML. However, the use of mIDH inhibitors in monotherapy usually leads to the development of resistance and the subsequent recurrence of the cancer, despite the initial effectiveness of the therapy. A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.