Acute Myeloid Leukemia Patients Research Articles

The expressions of myeloid differentiation and non-lineage specific differentiation antigens among FAB subtypes of acute myeloid leukemia in Iraqi patients

Background. Acute myeloid leukemia (AML) is a complex malignant disorder showing various subtypes with myeloid differentiation and non-lineage specific differentiation antigens (CD markers) expressions. Aim. The aim of this study is to evaluate the expression of myeloid and lymphoid antigens in relation to different French‑American‑British classification (FAB subtypes). Method. Three hundred and forty-four acute myeloid leukemia patients diagnosed based on blast percentage underwent bone marrow aspirate or whole blood collection, and flow cytometry was used to identify blast cells. Results. The expressions of myeloid differentiation antigens in AML patients were commonly observed; CD33 (73.3%), CD13 (68.3%), CD117 (67.4%), CD64 (54.6%), and cMPO (52.9%) in AML cases, with a significant difference in positivity (p-value < 0.05) among FAB classes (M0, M1, M2, M3, M4, M5, and M7). The expression of non-myeloid-associated antigen HLA-DR (34.01%) and CD34 (42.15%) showed high prevalence among FAB subtypes of AML. Regarding CD36 (13.3%), CD35 (13.08%), IREM2 (9.9%), and CD123 (9.01%), the expression was lower than HLA-DR and CD34, with no expression of CD38 in AML patients. A significant difference in expression and distribution of CD markers among AML subclasses was found (p<0.05). Conclusion. A large number of AML cases showed CD33 (73.3%), CD13 (68.3%), and CD117 (67.4%) expressions; these markers give two scores in diagnosis and highly distribution in AML subtype. Although no other leukemia subtypes were found to be linked to AML instances, AML blasts exhibited abnormal lymphoid characteristics, whereby the most prevailing lymphoid marker that was aberrantly expressed in AML was CD7. T-cell markers were more prevalent than B-cell markers.

IRX-related homeobox gene MKX is a novel oncogene in acute myeloid leukemia.

Homeobox genes encode transcription factors which organize differentiation processes in all tissue types including the hematopoietic compartment. Recently, we have reported physiological expression of TALE-class homeobox gene IRX1 in early myelopoiesis restricted to the megakaryocyte-erythroid-progenitor stage and in early B-cell development to the pro-B-cell stage. In contrast, sister homeobox genes IRX2, IRX3 and IRX5 are aberrantly activated in the corresponding malignancies acute myeloid leukemia (AML) and B-cell progenitor acute lymphoid leukemia. Here, we examined the role of IRX-related homeobox gene MKX (also termed IRXL1 or mohawk) in normal and malignant hematopoiesis. Screening of public datasets revealed silent MKX in normal myelopoiesis and B-cell differentiation, and aberrant expression in subsets of AML and multiple myeloma (MM) cell lines and patients. To investigate its dysregulation and oncogenic function we used AML cell line OCI-AML3 as model which strongly expressed MKX at both RNA and protein levels. We found that IRX5, JUNB and NFkB activated MKX in this cell line, while downregulated GATA2 and STAT5 inhibited its expression. MKX downstream analysis was conducted by siRNA-mediated knockdown and RNA-sequencing in OCI-AML3, and by comparative expression profiling analysis of a public dataset from MM patients. Analysis of these data revealed activation of CCL2 which in turn promoted proliferation. Furthermore, MKX upregulated SESN3 and downregulated BCL2L11, which may together underlie decreased etoposide-induced apoptosis. Finally, myeloid differentiation genes CEBPD and GATA2 were respectively up- and downregulated by MKX. Taken together, our study identified MKX as novel aberrantly expressed homeobox gene in AML and MM, highlighting the function of IRX1 in normal myelopoiesis and B-cell development, and of IRX-related genes in corresponding malignancies. Our data merit further investigation of MKX and its deregulated target genes to serve as novel markers and/or potential therapeutic targets in AML patient subsets.

Acute myeloid leukemia treatment outcomes with isocitrate dehydrogenase mutations: A systematic review and meta-analysis.

Isocitrate dehydrogenase (IDH) gene alterations and acute myeloid leukemia (AML) treatment results remain controversial. This study reviews the literature on IDH mutations in AML to determine the foundation of individualized therapy and improve effectiveness, survival time, and recurrence rate. Seven English and 2 Chinese databases were searched for literature on IDH mutations and AML outcomes. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Twenty studies were included in this analysis. For the prognostic influence of IDH mutation on AML patients, the pooled HRs of overall survival in AML patients were 0.76 (95% CI, 0.63-0.93); the pooled HRs of event-free survival were 1.34 (95% CI, 1.15-1.57; heterogeneity: I2 = 52.2%, P = .027 < 0.05); the pooled HRs of recurrence free survival were 0.79 (95% CI, 0.61-1.02). The pooled HRs of overall survival in AML patients with mutant IDH1 were 1.62 (95% CI, 1.42-1.86) and of mutant IDH2 were 1.07 (95% CI, 0.89-1.29). The pooled HRs for event-free survival in AML patients with mutant IDH1 were 1.71 (95% CI, 1.40-2.08) and of mutant IDH2 were 0.93 (95% CI, 0.65-1.34). No evidence of publication bias was observed. Different subtypes of IDH mutations may lead to different AML prognoses, suggesting the feasibility of personalized treatment for AML patients.

Clinical significance of dynamic monitoring of EVI1 gene expression in pediatric acute myeloid leukemia

ObjectiveTo investigate the clinical significance of dynamic monitoring ecotropic virus integration site-1 (EVI1) expression in childhood acute myeloid leukemia (AML).MethodsA retrospective analysis was conducted on 113 pediatric AML patients of Wuhan Children’s Hospital from 2014 to 2022. The correlation between EVI1 expression levels and clinical indicators including clinical characteristics, first complete remission (CR1), relapse, and overall survival (OS) was analyzed. Receiver operating characteristic (ROC) curve analysis was carried out to comprehend the influence of EVI1 expression on relapse.ResultsA total of 78 AML children with EVI1 expression at initial diagnosis were eligible, divided into EVI1-positive (EVI1high) and EVI1-negative (EVI1low) groups. FAB classification (P = 0.047) and abnormal karyotype (P = 0.009) showed significant differences between the two groups. The proportion of EVI1high in individuals with complex and/or monomeric karyotypes was significantly higher than in other cases (P = 0.032). When completing the first induction therapy, the EVI1high group showed a significantly lower CR1 rate than the EVI1low group (P = 0.015). Among 51 cases with EVI1 expression dynamically monitored, those with EVI1 overexpression more than twice had significantly shorter OS (P < 0.05). Among 19 non-HSCT patients undergoing three EVI1 assessments during induction therapy, those with EVI1 overexpression over once had higher relapse rates (P = 0.045). In addition, EVI1 expression level ≥ 83.38% significantly predicted relapse (AUC = 0.833).ConclusionAberrantly high expression of EVI1 in pediatric AML was associated with poor prognosis. Continuous and dynamic monitoring of EVI1 expression promotes prognostic evaluation. We add some insights into the impact of EVI1 on the AML patients’ OS and survival.

Single-cell transcriptome profiling of m6A regulator-mediated methylation modification patterns in elderly acute myeloid leukemia patients

Millions of people worldwide die of acute myeloid leukaemia (AML) each year. Although N6-methyladenosine (m6A) modification has been reported to regulate the pathogenicity of AML, the mechanisms by which m6A induces dysfunctional hematopoietic differentiation in elderly AML patients remain elusive. This study elucidates the mechanisms of the m6A landscape and the specific roles of m6A regulators in hematopoietic cells of elderly AML patients. Notably, fat mass and obesity-associated protein (FTO) was found to be upregulated in hematopoietic stem cells (HSCs), myeloid cells, and T-cells, where it inhibits their differentiation via the WNT signaling pathway. Additionally, elevated YT521-B homology domain family proteins 2 (YTHDF2) expression in erythrocytes was observed to negatively regulate differentiation through oxidative phosphorylation, resulting in leukocyte activation. Moreover, IGF2BP2 was significantly upregulated in myeloid cells, contributing to an aberrant chromosomal region and disrupted oxidative phosphorylation. m6A regulators were shown to induce abnormal cell-cell communication within hematopoietic cells, mediating ligand-receptor interactions across various cell types through the HMGB1-mediated pathway, thereby promoting AML progression. External validation was conducted using an independent single-cell RNA sequencing (scRNA-Seq) dataset. The THP-1 and MV411 cell lines were utilized to corroborate the m6A regulator profile; in vitro experiments involving short hairpin RNA (shRNA) targeting FTO demonstrated inhibition of cell proliferation, migration, and oxidative phosphorylation, alongside induction of cell cycle arrest and apoptosis. In summary, these findings suggest that the upregulation of m6A regulators in HSCs, erythrocytes, myeloid cells, and T-cells may contribute to the malignant differentiation observed in AML patients. This research provides novel insights into the pathogenesis of AML in elderly patients and identifies potential therapeutic targets.

Advantages of a genomic DNA-based NGS assay for detection of mutant NPM1 measurable residual disease in AML.

Mutations in the Nucleophosmin-1 (NPM1) gene are among the most common molecular aberrations in acute myeloid leukemia (AML). Various studies have established mutant NPM1 (mNPM1) as a faithful molecular measurable residual disease (MRD) marker with prognostic significance. Assessment of prognostic mNPM1 is included in the European LeukemiaNet (ELN) recommendations on MRD detection in AML. Due to recent advancements of promising drugs targeting mNPM1 AML, monitoring of mNPM1 MRD has gained interest, and is generally done by reverse transcriptase quantitative PCR (RT-qPCR). However, these RT-qPCR assays use cDNA as input, are based on gene expression levels of mNPM1, and are generally limited to specific mNPM1 gene variants. The main advantages of next-generation sequencing (NGS) using genomic DNA as input are stability, independence of gene expression levels, and the ability to detect any NPM1 variant in a single assay. Here we comprehensively investigated the applicability of NGS on DNA to detect mNPM1 MRD in a cohort of 119 (cDNA) and 310 (DNA) mNPM1 AML patients in complete remission after two cycles of induction chemotherapy. We demonstrate high correlations in levels and prognostic value between RT-qPCR/cDNA and NGS/DNA approaches, postulating NGS/DNA as an attractive alternative to RT-qPCR. We report that the 2% mNPM1/ABL1 threshold by RT-qPCR/cDNA corresponds to a NGS/DNA variant allele frequency (VAF) of 0.01%. The NGS/DNA threshold of >0.01% after two cycles of induction chemotherapy identifies significantly more AML patients with an increased relapse risk than current RT-qPCR/cDNA assays. The prognostic significance of mNPM1 MRD appears greatest in FLT3-ITD AML patients.

Identification of Potential Biomarkers and Pathways in Acute Myeloid Leukemia: Correlation Between the Calcineurin Signaling Pathway and Vascular Brittleness in Acute Myeloid Leukemia.

In this study, clinical bioinformatics analysis was used to identify potential biomarkers of acute myeloid leukemia (AML) occurrence and development, drug resistance, and poor prognosis to provide a theoretical basis for the treatment of AML. On the basis of the TCGA, GEO, and GTEx databases, an AML secondary database was established, and differential expression analysis and WGCNA were carried out to identify genes related to the prognosis of AML patients. Survival analysis was carried out for internal verification of key genes, and GEO data were used for external verification to obtain core genes related to prognosis. For differentially expressed genes, the EpiMed platform independently developed by the team was used for drug prediction. A total of 36 overlapping genes were obtained via difference analysis and WGCNA. Enrichment analysis revealed that the overlapping genes were associated with neutrophil activation, transcription dysregulation, AML, apoptosis, and other biological indicators. A protein interaction network was constructed for NCOA4, ACSL4, DPP4, ATL1, MT1G, ALOX15, and SLC7A11, which are key genes. Survival analysis revealed that NCOA4, ACSL4, DPP4, and ATL1 significantly affected the survival of patients with AML. The GSE142698 dataset verified that MPO, BCL2A1, and STMN1 had a statistically significant impact on the survival of AML patients. NCOA4, ACSL4, DPP4, and ATL1 may be potential biomarkers related to the survival and prognosis of patients with AML, and the calcineurin signaling pathway is associated with the risk of vascular fragility in AML patients, which can provide a reference for further research and optimization of treatment regimens.

Survival impact of hypoxia-inducible factor-1 alpha (HIF-1α) in Nucleophosmin1 mutated acute myeloid leukemia.

Nucleophosmin1 (NPM1) mutated acute myeloid leukemia (AML) without FLT3-ITD mutation is classified as a favorable risk AML which responds well to cytarabine therapy. Hypoxia-inducible factor-1 alpha (HIF-1α) promotes leukemic cell survival and maintains leukemic stem cell quiescence possibly contributing to cytarabine resistance. This study evaluated HIF-1α expression using immunohistochemistry in bone marrow of 29 newly diagnosed NPM1+FLT3-ITD- normal karyotype AML patients and analyzed its correlation with survival. All patients achieved complete remission after standard induction chemotherapy and proceeded to cytarabine consolidations. Positive HIF-1α staining with golgi body pattern and strong cytoplasmic HIF-1α expression was identified in 34.5% and 58.6% of patients, respectively. The expression of golgi body or strong cytoplasmic HIF-1α expression was related to increased relapse (p = 0.048) with significantly inferior relapse-free survival (RFS, p = 0.042). Using multivariate analysis, extramedullary disease at diagnosis was revealed as an independent prognostic factor for adverse RFS (hazard ratio [HR] 3.82; 95% confidence interval [CI] 1.26-11.55, p = 0.018), while golgi body or strong cytoplasmic HIF-1α expression showed a trend toward poor RFS (HR 3.56; 95% CI 1.00-12.69, p = 0.050). In summary, high HIF-1α expression is potentially a baseline prognostic biomarker for poor RFS and cytarabine resistance in NPM1+FLT3-ITD- AML. Further studies with the large number of patients are warranted.

Wilms’ Tumor 1 Gene Expression as a Predictive Marker for Clinical Outcome of Acute Myeloid Leukemia in Iraqi Population: A Prospective Study

Background: Wilms' tumor gene 1 (WT1), a tumor-associated antigen (TAA), is expressed in many types of cancer. Most acute leukemia patients have a quantitatively detectable and strong expression of it. Objectives: To analyze WT1 expression levels as a predictor of clinical outcomes at the time of diagnosis of de novo leukemia and to monitor tumor progression during treatment. Methods: A total of 71 patients with acute myeloid leukemia (AML) were separated into two groups: twenty-nine de novo AML patients upon presentation and 25 with AML at the time of initial induction. The second induction included 17 AML patients and ten healthy volunteers who served as controls in this study. The WT1 gene was tested using a real-time PCR with the Cyber Green assay. Results: Patients with acute myeloid leukemia had considerably greater levels of WT1 gene expression than controls (27.3 vs. 5.5). In terms of clinical outcomes, WT1 gene overexpression was substantially related to non-responsive AML patients compared to complete response at diagnosis (27.3 vs. 22.15). However, there is no substantial difference between instances following induction. Conclusions: The WT1 tumor antigen may serve as an early diagnostic for acute leukemia prognosis. Improved clinical outcomes have been linked to reduced WT1 levels. A high amount, on the other hand, was linked to a poor prognosis for people with AML, although more research is needed.

Population pharmacokinetic analysis of quizartinib in patients with newly diagnosed FLT3-internal-tandem-duplication-positive acute myeloid leukemia.

The population pharmacokinetics (PK) of quizartinib and its pharmacologically active metabolite AC886 have been previously described in healthy volunteers (HV) and relapsed/refractory (R/R) FLT3-internal-tandem-duplication-positive (FLT3-IDT-positive) acute myeloid leukemia (AML) patients receiving quizartinib monotherapy. In this analysis, we characterized the population PK of quizartinib and AC886 in newly diagnosed FLT3-ITD-positive AML patients receiving standard induction and consolidation chemotherapy as background treatment, using data from the Phase 3 QuANTUM-First trial and 12 earlier studies. Quizartinib PK were best described by a three-compartment model with sequential zero- and first-order absorption and first-order elimination. A two-compartment model with first-order metabolite formation and first-order elimination best fitted AC886 data. The PK of both moieties showed large interindividual variability (approximately 70% coefficient of variation for systemic clearances). The use of strong cytochrome P450 3A (CYP3A) inhibitors had the largest impact on exposure, increasing the steady-state area under the curve during the dosing interval (AUCss) by 1.8-fold. This is consistent with observations in HV and R/R AML patients and confirms the need for dose adjustments during coadministration. A novel finding in newly diagnosed AML patients was the phase-dependent change in steady-state quizartinib exposure: dose-normalized AUCss values were 0.6-fold during induction, similar during consolidation, and 1.4-fold during continuation compared to R/R AML patients receiving quizartinib monotherapy. The present analysis highlighted the comparison of quizartinib and AC886 PK between newly diagnosed AML patients and previously studied populations, informed dose modifications needed with strong CYP3A inhibitors, and supported the use of derived individual exposure metrics in separate exposure-response analyses.

Integrated Analysis of Polymerase Family Gene Mutations in Acute Myeloid Leukemia: Clinical Features, Prognosis, and Bioinformatics Insights

Background and Objectives: The long-term prognosis of acute myeloid leukemia (AML) is challenging due to limited understanding of the molecular markers involved in its development. This study investigates the role of DNA polymerases in AML to offer new insights for diagnosis and treatment. Materials and Methods: A retrospective study on pediatric AML patients with POL gene family mutations from 2021 to 2024 was conducted. Patients were categorized based on risk stratification criteria, and the DAH regimen was used for induction chemotherapy. Bioinformatics analysis integrated data from various databases to identify key genes and develop survival analysis plots and AUC curves. Results: The study included 59 pediatric AML patients, revealing no significant differences in demographic or clinical characteristics between those with and without POL family gene mutations. However, patients with POL gene mutations showed higher complete remission rates after initial DAH chemotherapy (91.67% vs. 59.57%, p = 0.03607), indicating a potential treatment benefit. High expression of four POL genes (POLD1, POLE, POLG, and POLQ) in bone marrow and immune cells suggests their crucial role in hematopoiesis and immune response. Survival analysis across different datasets indicated that AML patients with overexpressed POL family genes had significantly worse outcomes, proposing these genes as potential prognostic biomarkers for AML. Conclusions: This study on pediatric AML demonstrates that POL gene family mutations are associated with higher remission rates post-chemotherapy, indicating their potential as prognostic markers. Bioinformatics analysis emphasizes the significance of these mutations in AML, highlighting their impact on disease prognosis.

Inhibition of Acute Myeloid Leukaemia Development by Bittersweet Based on miR-let-7a Regulating Vascular Endothelial Growth Factor A Resistance Mechanism

Acute myeloid leukaemia (AML) is closely related to regulation of miR-let-7a and vascular endothelial growth factor A (VEGFA). Picrasidine is a traditional Chinese medicine extract with antitumour effects, but its mechanism of action in AML is unclear. This study investigated picloram’s effect on AML and its relationship with miR-let-7a regulation of VEGFA resistance mechanism. Bone marrow samples from leukaemia patients in the Department of Haematology of our hospital were collected, and RT-PCR detected miR-let-7a and VEGFA expression in the bone marrow of healthy individuals and leukaemia patients. At the same time, cell culture of AML-resistant cell line K562/ADM was performed, which was divided into NC group, Picrasidine L group, Picrasidine M group, Picrasidine H group, si-NC group, Picrasidine H+miR-let-7a inhibitor group, Picrasidine H+miR-let-7a mimic group, miR-let-7a mimic+hVEGF-IN-1 group, miR-let-7a inhibitor+hVEGF-IN-1 group, and Picrasidine H+miR-let-7a mimic+hVEGF-IN-1 group. Cell proliferation and apoptosis was detected and correlation between miR-let-7a and VEGFA was analyzed by clinical samples. Picrasidine had a significant ameliorative effect on acute myeloid leukaemia in a dose-dependent manner. miR-let-7a was lowly expressed and VEGFA was highly expressed in AML patients. miR-let-7a and VEGFA showed significant correlation in human AML disease staging, and there was a statistically significant difference (p &lt;0.05). That is to say, picloram promotes miR-let-7a expression, thus achieving inhibition of VEGFA, which in turn promotes apoptosis of AML drug-resistant cell line K562/ADM and inhibits its proliferation. The ameliorative effect of Picrasidine on acute myeloid leukaemia was achieved by upregulating miR-let-7a and downregulating VEGFA.

The Clinical Impact of NPM1 Mutations and the Effect of Concurrent Mutations in Acute Myeloid Leukemia: Unraveling the Prognostic Significance.

Nucleophosmin (NPM1) gene mutations occur in approximately 30%-35% of individuals with an initial diagnosis of acute myeloid leukemia (AML). Mutations in this gene have been reported in 50%-60% of AML patients with a normal karyotype. These mutations help to distinguish clinicopathological and molecular features, setting them apart as a unique subset within the heterogeneous landscape of AML. In the present study, we investigated the frequency and clinical impact of NPM1 mut in 100 newly diagnosed adult Syrian patients with AML-normal karyotype (NK) using direct sequencing. We analyzed 100 AML-NK patients using direct sequencing to assess the prevalence and clinical impact of NPM1 mutations, as well as the co-occurrence of FLT3-ITD and DNMT3A mutations. Our results revealed that the prevalence of NPM1 mut was 22% among the patients; 86.4% of these mutations were type A (NM_002520.5:c.860-863dupTCTG), while 13.6% were de novo mutations (c.863_864insCCTG, p.Trp288CysfsTer12), (c.861_862dup, p.Trp288SerfsTer13), and (c.863_864insCCGG, p.Trp288CysfsTer12). Among our patients, 22% exhibited NPM1 mut, with 7% also harboring FLT3-ITD mut and 2% having DNMT3A mut. The presence of NPM1 mut was correlated with a statistically significant increase in bone marrow blast percentage (p = 0.017). Notably, patients with NPM1 mut displayed significantly higher mortality rates, with 72.7% succumbing to the disease compared to 29.5% of patients without NPM1 mut (p < 0.001). Furthermore, our results showed that when the overall survival (OS) time exceeded 8.35 months, the likelihood of NPM1 wild-type status was greater. The evaluation of NPM1 mut and co-mutation has consistently demonstrated remarkable prognostic significance in AML, suggesting the potential for improved response rates, extended disease-free periods, and OS. Our findings provide valuable insights for understanding molecular leukemogenesis in AML-NK patients and will aid in clinical diagnosis, prognostic implications, and the development of targeted therapy strategies for Syrian AML patients.

The Dual PIM/FLT3 Inhibitor MEN1703 Combines Synergistically With Gilteritinib in FLT3-ITD-Mutant Acute Myeloid Leukaemia.

MEN1703 is a first-in-class, oral, Type I dual PIM/FMS-like tyrosine kinase 3 inhibitor (FLT3i) investigated in a Phase I/II DIAMOND-01 trial in patients with acute myeloid leukaemia (AML). Gilteritinib is a highly potent and selective oral FLT3i approved for the treatment of relapsed/refractory AML with FLT3 mutations. Although gilteritinib showed strong single-agent activity in FLT3-mutated AML, the development of gilteritinib resistance limits response durability, indicating the importance of novel combination strategies to improve disease outcome. PIM kinases govern FLT3-ITD signalling and increased PIM kinase expression is found in samples from AML patients relapsing on FLT3i. Here, we report that the simultaneous inhibition of PIM and FLT3, through the combination of MEN1703 and gilteritinib, can consistently improve the invitro/in vivo antitumor activity over the single agents, demonstrating the benefit of this combination. Moreover, we demonstrate that resistance to gilteritinib can be circumvented by combining MEN1703 with gilteritinib. MEN1703 interferes with FLT3 upregulation, Mcl-1 overexpression and PIM kinase signalling, which are all involved in FLT3i resistance. We also show that MEN1703 downregulates stromal cytokines that promote cytokine-mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment-mediated resistance to FLT3 inhibitors.

Combination Therapy Involving Azacitidine for Acute Myeloid Leukemia Patients Ineligible for Intensive Chemotherapy

Combination Therapy Involving Azacitidine for Acute Myeloid Leukemia Patients Ineligible for Intensive Chemotherapy

Emerging functions of FMNL1 in myeloid neoplasms: insights from bioinformatics to biological and pharmacological landscapes.

Myeloid neoplasms encompass disorders characterized by abnormal myeloid cell proliferation and differentiation, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Formin-like protein 1 (FMNL1) is involved in the regulation of the actin cytoskeleton and is predominantly expressed in hematopoietic cells. Given its role in leukemia cell proliferation, survival, migration, and invasion, this study investigates FMNL1 expression in normal hematopoiesis and myeloid neoplasms and explores associations with clinical-laboratory characteristics, mutational status, and survival outcomes in AML. Transcript levels of FMNL1 from several blood-forming cell populations and myeloid neoplasms were extracted from publicly available databases. Myeloid neoplasm cell lines were used for gene/protein expression and cell differentiation studies. Functional genomics analysis was performed using RNA-seq data from The Cancer Genome Atlas (TCGA) AML study, and drug sensitivity predictions were investigated using Beat AML and Genomics of Drug Sensitivity in Cancer (GDSC) datasets. Statistical analyses assessed the impact of FMNL1 expression on clinical outcomes. FMNL1 was highly expressed in metamyelocytes, neutrophils, and monocytes compared to hematopoietic stem cells, and its expression increased with granulocytic differentiation. FMNL1 expression was elevated in AML and CML patients compared to healthy donors. FMNL1 expression was not significantly associated with clinical-laboratory characteristics or survival outcomes but showed a higher frequency of WT1 transcription factor (WT1) mutations with low FMNL1 expression in AML patients. High FMNL1 expression in AML correlated with immune response and inflammatory activity pathways. FMNL1 mRNA levels influenced drug sensitivity in AML models, with correlations observed for specific antineoplastic agents. FMNL1 plays a potential role in granulocyte differentiation and function, and its differential expression is linked to critical signaling pathways in leukemogenesis and inflammation. These findings highlight FMNL1's potential therapeutic implications in myeloid neoplasia, warranting further investigation.

FLT3 mutation-related immune checkpoint molecule absent in melanoma 2 (AIM2) contributes to immune infiltration in pediatric and adult acute myeloid leukemia: evidence from bioinformatics analysis.

The use of FMS-like tyrosine kinase 3 (FLT3) as a crucial target for kinase inhibitors is well established, but its association with immune infiltration remains unclear. This study aimed to explore the relationship between FLT3 mutations and immune checkpoint molecules (ICMs) in patients with acute myeloid leukemia (AML). The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases were used to identify the ICMs associated with FLT3 mutations. A Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted to analyze the signaling pathways related to the ICMs. The single-sample GSEA (ssGSEA), Cibersort, and estimate algorithms were used to assess immune cell infiltration in AML. Absent in melanoma 2 (AIM2) exhibits elevated expression levels in AML patients harboring FLT3 mutation, contributing significantly to the progress of AML and establishing of an immunosuppressive microenvironment. AIM2 expression significantly correlated with sensitivity of clinically relevant drugs in ex vivo assays of AML. Additionally, AIM2 demonstrates substantial prognostic value and holds promise as a prospective immunotherapeutic target for AML. Our findings indicate a significant correlation between AIM2 and immune infiltration in AML cases, potentially affecting the presence of neutrophils, macrophages, effector memory T cells (Tem), and monocytes. Furthermore, AIM2 is closely linked to various signaling pathways, such as immune cytokine release, immune antigen presentation, and inflammasome signaling, which could play a role in immune cell enrichment in AML. Our study identified AMI2 as an ICM linked to FLT3 mutations. AMI2 may be involved in the activation of suppressive immune cell populations, such as macrophages, neutrophils, and monocytes. AIM2 could serve as a promising immunotherapeutic target for combination therapy with FLT3 inhibitors in AML.

Inhibition of TOX exerts anti-tumor effects in acute myeloid leukemia by upregulating IRF7 expression

Thymocyte selection-associated high mobility group box protein (TOX) is regarded as a crucial transcription factor involved in T cell exhaustion in acute myeloid leukemia (AML). Previous studies have identified aberrant TOX expression as a major oncogenic driver in hematologic malignancies, indicating that TOX may potentially be both an immune biomarker and an immunotherapy target. However, due to heterogeneity in the distribution patterns of TOX and its correlation with clinical prognosis, the mechanism underlying TOX-mediated tumor immune responses remains unclear. In this study, we demonstrate that high TOX expression in AML patients is associated with poor prognosis, and TOX overexpression promotes AML cell proliferation and restricts apoptosis. In vitro TOX inhibition promoted the apoptosis of AML cells, suppressed cell viability, and induced cell cycle arrest in the G0/G1 phase. Moreover, TOX knockdown could reduce tumor burden in vivo in immunodeficient mice and prolong their survival. Furthermore, the anti-AML effects of inhibiting TOX may act through activation of the IFN-α signal pathway and upregulating IRF7 expression. In summary, we report for the first time that TOX knockdown exerts powerful anti-tumor effects in AML. These findings will provide a theoretical basis for targeted therapy in AML patients.

Pharmacological inhibition of ezrin reduces proliferative and invasive phenotype in acute lymphoblastic leukemia cells

Ezrin (EZR) is an actin-associated protein that is often upregulated in cancers. Here we investigate the role of EZR in acute lymphoblastic leukemia (ALL) and explore the therapeutic potential of a pharmacological EZR inhibitor, NSC305787. ALL patient cohorts exhibit significantly elevated EZR mRNA levels, indicating its association with the malignant phenotype. Notably, EZR expression does not impact survival outcomes or relevant clinical-laboratory characteristics, suggesting a role in disease initiation rather than therapy response. NSC305787 induces a dose-dependent reduction in ALL cell viability, and is more potent than a related EZR inhibitor, NSC668394. NSC305787 has multiple effects on ALL cells, including apoptosis induction, clonal growth reduction, and inhibition of cell cycle progression. Importantly, it diminishes adhesiveness and invasiveness in ALL cells. Proteomics analysis highlights changes in translation, RNA catabolism, and cell cycle regulation, emphasizing the broad impact of EZR inhibition on ALL cell biology. Ex vivo assays with primary cells from acute myeloid leukemia (AML) and ALL patients demonstrate NSC305787's efficacy across a molecularly heterogeneous group, independent of risk stratification or recurrent mutations. Notably, NSC305787 shows heightened potency in ALL cells, suggesting its potential as a targeted therapy. In conclusion, our results report high EZR expression in adult ALL patients and support NSC305787 as a promising targeted therapy for ALL that should be further explored.

A next generation probabilistic approach to analyze cancer patients data with inference and applications

This study addresses the critical challenges faced in cancer care, particularly in predicting survival times for patients with lung cancer and acute myeloid leukemia. Despite recent advancements in medical science, existing models often fall short in accurately capturing disease progression, leading to less effective clinical decision-making, and compromised patient outcomes. The need for advanced predictive models is urgent to improve survival time forecasts and enhance treatment strategies. In response to this, we introduce a novel probabilistic approach, the New Weibull (NEWE) model, which is part of a newly generated class designed to model cancer patient data more effectively. Our methodology includes using seven well-known estimation methods, each rigorously evaluated for consistency through Monte Carlo simulation studies focused on key metrics such as absolute bias, mean square error, and mean relative error. The datasets analyzed include survival times for twenty acute myeloid leukemia patients, 121 breast cancer patients from 1929 to 1938, 33 patients with acute myelogenous leukemia, data from eighteen individuals who died from causes unrelated to cancer, and survival times of advanced lung cancer patients undergoing standard chemotherapy. The NEWE model outperformed competing models, particularly in Anderson-Darling, Cramer-von Mises, and Kolmogorov-Smirnov tests, with significantly higher p-values. These findings highlight the NEWE model’s potential to transform predictive oncology by offering more precise survival time predictions, improving the quality of care and decision-making in cancer treatment.