Progression To Acute Myeloid Leukemia Research Articles

METTL14-mediated N6-methyladenosine modification of TCP1 mRNA promotes acute myeloid leukemia progression

BackgroundAcute myeloid leukemia (AML) is a prevalent hematologic malignancy characterized by a steady rise in morbidity and mortality rates over time. The upregulation of methyltransferase-like 14 (METTL14) expression in AML has been identified; however, its specific contributions to AML progression and underlying molecular mechanisms have yet to be elucidated. MethodMETTL14-bound mRNAs were predicted using bioinformatics methods, analyzed, and screened to identify T-complex protein 1 (TCP1). The regulatory impact of METTL14 on TCP1 was observed. TCP1 expression in AML clinical samples was assessed using quantitative real-time PCR and western blot analysis. The involvement of TCP1 in AML malignant progression was assessed through in vitro and in vivo functional assays. The String database was utilized for predicting proteins that interact with TCP1, while western blot assays and immunoprecipitation were employed to validate the associated signaling pathways. ResultsMETTL14 overexpression upregulates TCP1 expression in AML cells. AML patients exhibit high levels of TCP1 expression. Elevated TCP1 levels in HL60 and U937 cells in vitro lead to increased proliferation, migration, invasion, and inhibition of apoptosis, while in vivo, it accelerates AML proliferation and tumorigenesis. Mechanistically, METTL14 modulates AML progression by influencing TCP1 transcript stability via m6A methylation, thereby regulating TCP1 expression. Additionally, PPP2R2C potentially serves as a crucial functional target of TCP1 implicated in the malignant progression of AML. ConclusionUpregulation of TCP1 expression in AML through METTL14-mediated m6A modification accelerates the malignant progression of the disease. Therefore, targeting the m6A modification of TCP1 could be a potential therapeutic strategy to enhance the treatment of AML.

MICAL1 promotes the proliferation in acute myeloid leukemia and is associated with clinical prognosis and immune infiltration

Acute myeloid leukemia (AML) is one of the most common hematopoietic malignancies that has a poor prognosis and a high rate of relapse. Dysregulated metabolism plays an important role in AML progression. This study aimed to conduct a comprehensive analysis of MRGs using TCGA and GEO datasets and further explore the potential function of critical MRGs in AML progression. In this study, we identified 17 survival-related differentially expressed MRGs in AML using TCGA and GEO datasets. The 150 AML samples were divided into three molecular subtypes using 17 MRGs, and we found that three molecular subtypes exhibited a different association with ferroptosis, cuproptosis and m6A related genes. Moreover, a prognostic signature that comprised nine MRGs and had good predictive capacity was established by LASSO-Cox stepwise regression analysis. Among the 17 MRGs, our attention focused on MICAL1 which was highly expressed in many types of tumors, including AML and its overexpression was also confirmed in several AML cell lines. We also found that the expression of MICAL1 was associated with several immune cells. Moreover, functional experiments revealed that knockdown of MICAL1 distinctly suppressed the proliferation of AML cells. Overall, this study not only contributes to a deeper understanding of the molecular mechanisms underlying AML but also provides potential targets and prognostic markers for AML treatment. These findings offer robust support for further research into therapeutic strategies and mechanisms related to AML, with the potential to improve the prognosis and quality of life for AML patients. Nevertheless, further research is needed to validate these findings and explore more in-depth molecular mechanisms.

SLPI overexpression in hMSCs could be implicated in the HSC gene expression profile in AML

Acute myeloid leukaemia (AML) is a severe haematological neoplasm that originates from the transformation of haematopoietic stem cells (HSCs) into leukaemic stem cells (LSCs). The bone marrow (BM) microenvironment, particularly that of mesenchymal stromal cells (hMSCs), plays a crucial role in the maintenance of HSCs. In this context, we explored whether alterations in the secretome of hMSCs derived from AML patients (hMSC-AML) could impact HSC gene expression. Proteomic analysis revealed that the secretome of coculture assays with hMSC-AMLs and HSC from healthy donor is altered, with increased levels of secretory leukocyte protease inhibitor (SLPI), a protein associated with important processes for maintenance of the haematopoietic niche that has already been described to be altered in several tumours. Increased SLPI expression was also observed in the BM plasma of AML patients. Transcriptome analysis of HSCs cocultured with hMSC-AML in comparison with HSCs cocultured with hMSC-HD revealed altered expression of SLPI target genes associated with the cell cycle, proliferation, and apoptosis. Important changes were identified, such as increased expression levels of CCNA2, CCNE2, CCND2, CD133 and CDK1 and decreased levels of CDKN2A and IGFBP3, among others. Overall, these findings suggest that the altered secretome of coculture assays with hMSC-AMLs and HSC from healthy donor, particularly increased SLPI expression, can contribute to gene expression changes in HSCs, potentially influencing important molecular mechanisms related to AML development and progression.

Condensate-Promoting ENL Mutation Drives Tumorigenesis In Vivo Through Dynamic Regulation of Histone Modifications and Gene Expression.

Gain-of-function mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL), found in acute myeloid leukemia (AML) and Wilms tumor, are known to drive condensate formation and gene activation in cellular systems. However, their role in tumorigenesis remains unclear. Using a conditional knock-in mouse model, we show that mutant ENL perturbs normal hematopoiesis, induces aberrant expansion of myeloid progenitors, and triggers rapid onset of aggressive AML. Mutant ENL alters developmental and inflammatory gene programs in part by remodeling histone modifications. Mutant ENL forms condensates in hematopoietic stem/progenitor cells at key leukemogenic genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Moreover, treatment with an acetyl-binding inhibitor of the mutant ENL displaces these condensates from target loci, inhibits mutant ENL-induced chromatin changes, and delays AML initiation and progression in vivo. Our study elucidates the function of ENL mutations in chromatin regulation and tumorigenesis and demonstrates the potential of targeting pathogenic condensates in cancer treatment. Significance: A direct link between ENL mutations, condensate formation, and tumorigenesis is lacking. This study elucidates the function and mechanism of ENL mutations in leukemogenesis, establishing these mutations as bona fide oncogenic drivers. Our results also support the role of condensate dysregulation in cancer and reveal strategies to target pathogenic condensates.

Recent Advances in Immune-Based Therapies for Acute Myeloid Leukemia.

Despite advancements, acute myeloid leukemia (AML) remains unconquered by current therapies. Evidence of immune evasion during AML progression, such as HLA loss and T-cell exhaustion, suggests that antileukemic immune responses contribute to disease control and could be harnessed by immunotherapy. In this review, we discuss a spectrum of AML immunotherapy targets, encompassing cancer cell-intrinsic and surface antigens as well as targeting in the leukemic milieu, and how they can be tailored for personalized approaches. These targets are overviewed across major immunotherapy modalities applied to AML: immune checkpoint inhibitors, antibody-drug conjugates, therapeutic vaccines, bispecific/trispecific antibodies, and chimeric antigen receptor (CAR)-T and CAR-NK cells. Significance: Immune therapies in AML treatment show evolving promise. Ongoing research aims to customize approaches for varied patient profiles and clinical scenarios. This review covers immune surveillance mechanisms, therapy options like checkpoint inhibitors, antibodies, CAR-T/NK cells, and vaccines, as well as resistance mechanisms and microenvironment considerations.

The impact of COVID-19 on microRNA and CD marker expression in AML patients

Acute myeloid leukaemia (AML) is an aggressive leukaemia characterised by uncontrolled blast cell proliferation. miRNAs and Clusters of Differentiation (CD) molecules play essential roles in AML progression. This study aims to investigate the effect of COVID-19 on the expression of circulating miRNA and CD molecules in AML. This cross-sectional study recruited 32 AML patients and 20 controls. Blood samples were collected and analysed using molecular cytogenetic, miRNA/mRNA expression, and flow cytometry techniques. The expression of miRNAs varied significantly between patients with AML and control individuals. The co-expression of these miRNAs was higher (P < 0.05), indicating that the presence of one miRNA led to increased expression of other miRNAs. A differential correlation was observed between miRNAs and CD markers. Additionally, miRNA 16, miRNA 21, and miRNA 221 showed significant downregulation (P < 0.05 and P < 0.01, respectively) in AML patients with COVID-19 infection compared to those without a disease. Interestingly, this study identified a higher expression level (P < 0.01) of miRNA 137 as a novel biomarker for AML patients. Moreover, the expression of miRNA 137 showed a high correlation (P < 0.05) with most of the CD markers examined in this study and FISH features data. Furthermore, a strong correlation (P < 0.01) was observed between CD markers and miRNA among AML patients with positive and negative COVID-19 infection. These data demonstrated that COVID-19 contributed to increased expression of microRNAs in AML patients. MicroRNA 137 was identified as a novel microRNA that exhibited significant differences between patients and healthy individuals, highlighting its role in AML pathogenesis.

Crosstalk between circBMI1 and miR-338-5p/ID4 inhibits acute myeloid leukemia progression.

BMI1 polycomb ring finger proto-oncogene (BMI1) is involved in the pathogenesis of different cancers, including acute myeloid leukemia (AML). However, the role of the circular RNA of BMI1 (circBMI1) has not been studied. Our study aimed to investigate the role and mechanism of circBMI1 in AML. circBMI1 was significantly decreased in bone marrow mononuclear cells aspirated from patients with AML. Receiver operating characteristic curve analysis showed that circBMI1 could distinguish patients with AML from controls. By overexpressing and knocking down circBMI1 in HL-60 cells, we found that circBMI1 inhibited cell proliferation, promoted apoptosis, and increased chemotherapeutic drug sensitivity in AML. Experiments using severe combined immune-deficient mice and circBMI1 transgenic mice showed that mice with circBMI1 overexpression had lower white blood cell counts, which suggested less severe AML invasion. RNA immunoprecipitation and dual-luciferase reporter assay revealed binding sites among circBMI1, miR-338-5p, and inhibitor of DNA-binding protein 4 (ID4). Rescue experiments proved that circBMI1 inhibited AML progression by binding to miR-338-5p, which affected the expression of ID4. By coculturing exosomes extracted from circBMI1-HL-60 and small interfering circBMI1-HL-60 cells with HL-60 cells, we found that exosomes from circBMI1-HL-60 cells showed tumor-suppressive effects, namely inhibiting HL-60 proliferation, promoting apoptosis, and increasing chemotherapeutic drug sensitivity. Exosomes from small interfering circBMI1-HL-60 cells showed the opposite effects. circBMI1 may act as an exosome-dependent tumor inhibitor. circBMI1, a potential biomarker for clinical diagnosis, acts as a tumor suppressor in AML by regulating miR-338-5p/ID4 and might affect the pathogenesis of AML by exosome secretion.

Integrative proteome analysis of bone marrow interstitial fluid and serum reveals candidate signature for acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive form of blood cancer and clinically highly heterogeneous characterized by the accumulation of clonally proliferative immature precursors of myeloid lineage leading to bone marrow failure. Although, the current diagnostic methods for AML consist of cytogenetic and molecular assessment, there is a need for new markers that can serve as useful candidates in diagnosis, prognosis and understanding the pathophysiology of the disease. This study involves the investigation of alterations in the bone marrow interstitial fluid and serum proteome of AML patients compared to controls using label-free quantitative proteomic approach. A total of 201 differentially abundant proteins were identified in AML BMIF, while in the case of serum 123 differentially abundant proteins were identified. The bioinformatics analysis performed using IPA revealed several altered pathways including FAK signalling, IL-12 signalling and production of macrophages etc. Verification experiments were performed in a fresh independent cohort of samples using MRM assays led to the identification of a panel of three proteins viz., PPBP, APOH, ENOA which were further validated in a new cohort of serum samples by ELISA. The three-protein panel could be helpful in the diagnosis, prognosis and understanding of the pathophysiology of AML in the future. Biological SignificanceAcute Myeloid Leukemia (AML) is a type haematological malignancy which constitute one third of total leukemias and it is the most common acute leukemia in adults. In the current clinical practice, the evaluation of diagnosis and progression of AML is largely based on morphologic, immunophenotypic, cytogenetic and molecular assessment. There is a need for new markers/signatures which can serve as useful candidates in diagnosis and prognosis. The present study aims to identify and validate candidate biosignature for AML which can be useful in diagnosis, prognosis and understand the pathophysiology of the disease. Here, we identified 201 altered proteins in AML BMIF and 123 in serum. Among these altered proteins, a set of three proteins viz., pro-platelet basic protein (CXCL7), enolase 1 (ENO1) and beta-2-glycoprotein 1 (APOH) were significantly increased in AML BMIF and serum suggest that this panel of proteins could help in future AML disease management and thereby improving the survival expectancy of AML patients.

RHOF activation of AKT/β-catenin signaling pathway drives acute myeloid leukemia progression and chemotherapy resistance

Acute myeloid leukemia (AML) is a clonal malignancy originating from leukemia stem cells, characterized by a poor prognosis, underscoring the necessity for novel therapeutic targets and treatment methodologies. This study focuses on Ras homolog family member F, filopodia associated (RHOF), a Rho guanosine triphosphatase (GTPase) family member. We found that RHOF is overexpressed in AML, correlating with an adverse prognosis. Our gain- and loss-of-function experiments revealed that RHOF overexpression enhances proliferation and impedes apoptosis in AML cells invitro. Conversely, genetic suppression of RHOF markedly reduced the leukemia burden in a human AML xenograft mouse model. Furthermore, we investigated the synergistic effect of RHOF downregulation and chemotherapy, demonstrating significant therapeutic efficacy invivo. Mechanistically, RHOF activates the AKT/β-catenin signaling pathway, thereby accelerating the progression of AML. Our findings elucidate the pivotal role of RHOF in AML pathogenesis and propose RHOF inhibition as a promising therapeutic approach for AML management.

Interim safety and efficacy of BP1001 in a phase II acute myeloid leukemia (AML) study.

6511 Background: Oncogenic tyrosine kinases induce AML progression via the growth factor receptor bound protein-2 (Grb2). BP1001, a liposome-incorporated Grb2 antisense oligonucleotide,enhanced cancer cell sensitivity to chemotherapy, such as decitabine (DEC) and venetoclax (VEN). A multi-center open-label Phase II study was initiated to assess whether the BP1001 + DEC + VEN combination provides higher response rates than historically reported responses of DEC + VEN in newly diagnosed AML (including secondary AML) (cohort 1) or refractory/relapsed (R/R; cohort 2) AML patients (pts) considered unsuitable for intensive chemotherapy. Per protocol, when 19 evaluable pts are enrolled in each cohort, interim analysis will be performed to determine which cohort has ≥5 complete responses and will continue with enrollment. Methods: BP1001 was given, beginning on Day 4, at 60 mg/m2 IV, 2x weekly for a total of 8 doses over a 28-day cycle. DEC was given IV on days 1 to 5 at 20 mg/m2. VEN was given PO at 100 mg on day 1, 200 mg on day 2, and 400 mg from day 3 to day 14 or 21. Eligible pts were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Interim analysis was performed on Jan 24, 2024 on pts enrolled between July 28, 2020 and December 26, 2023. Evaluability for efficacy was defined as: completion of at least 4 cycles of combination therapy, documented Progressive Disease (PD) or any drug toxicity at any time, or CR/CRi/CRh prior to 4 cycles. Results: In Cohort 1, 31 newly diagnosed pts were enrolled; 20 evaluable pts (9 male: 45%) with a median age of 75 years (range, 69 - 84), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=12, ELN 2017 classification) or secondary AML (sAML; n=7) evolved from MDS (n=4), CMML (n=1) or treatment-related AML (n=2). Fifteen pts (75% of evaluable; 54% of enrolled) achieved CR/CRi/CRh; 2 pts achieved partial remission (PR) and 2 achieved stable disease (SD). In Cohort 2, 38 R/R pts were enrolled; 23 evaluable pts (13 male: 57%) with a median age of 63 years (range, 24 - 89), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=13) or sAML (n=5). Twelve pts (55% of evaluable; 32% of enrolled) achieved CR/CRi/CRh; 1 pt achieved PR, 8 achieved SD and 1 had treatment failure. Among the evaluable pts of both cohorts, adverse events were consistent with those expected with DEC, VEN and/or AML, including fatigue (72%), anemia (60%) and neutropenia (49%), while the most frequent serious adverse events were febrile neutropenia (26%) and sepsis (5%). Conclusions: BP1001 + DEC + VEN has been safely administered to pts without drug-related toxicity. Since &gt;5 responses are observed in both cohorts, the study will continue with enrollment up to 98 and 54 evaluable pts in cohorts 1 and 2, respectively. Efficacy data are encouraging in a challenging population of frontline adverse-risk, sAML and R/R pts. Clinical trial information: NCT02781883 .

Circ_0012152 Accelerates Acute Myeloid Leukemia Progression through the miR-652-3p/SOX4 Axis.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by abnormal myeloid blast expansion. Recent studies have demonstrated that circular RNAs play a role in AML pathogenesis. In this study, we aimed to investigate the clinical significance of circ_0012152 in AML and elucidate its underlying molecular mechanism in the pathogenesis of this condition. Circ_0012152 expression was detected by quantitative real-time polymerase chain reaction in samples obtained from 247 patients with AML and 40 healthy controls. A systematic analysis of clinical characteristics and prognostic factors was also conducted. Cell growth was assessed using the Cell Counting Kit-8 (CCK-8) assay, and apoptosis and cell cycle progression were evaluated by flow cytometry. Moreover, RNA pull-down was performed to identify target microRNAs, and transcriptome RNA sequencing and bioinformatics analyses were utilized to identify downstream mRNA targets. Circ_0012152 was significantly upregulated in samples from patients with AML and served as an independent adverse prognostic factor for overall survival (OS) (hazard ratio: 2.357; 95% confidence interval 1.258-4.415). The circ_0012152 knockdown reduced cell growth, increased apoptosis, and inhibited cell cycle progression in AML cell lines. RNA pull-down and sequencing identified miR-652-3p as a target microRNA of circ_0012152. Cell growth inhibition by circ_0012152 knockdown was significantly relieved by miR-652-3p inhibitors. We suggested that miR-652-3p targeted SOX4, as the decrease in SOX4 expression resulting from circ_0012152 knockdown was upregulated by miR-652-3p inhibitors in AML cells. Circ_0012152 is an independent poor prognostic factor for OS in AML, and it promotes AML cell growth by upregulating SOX4 through miR-652-3p.

P200CUX1-regulated BMP8B inhibits the progression of acute myeloid leukemia via the MAPK signaling pathway.

The full-length p200CUX1 protein encoded by the homology frame CUT-like protein (CUX1) plays an important role in tumors as a pro-oncogene or oncogene. However, its role and mechanism in acute myeloid leukemia remain unknown. p200CUX1 regulates several pathways, including the MAPK signaling pathway. Our data showed that p200CUX1 is lowly expressed in THP1 and U937 AML cell lines. Lentiviral overexpression of p200CUX1 reduced proliferation and promoted apoptosis and G0/G1 phase blockade, correlating with MAPK pathway suppression. Additionally, p200CUX1 regulated the expression of bone morphogenetic protein 8B (BMP8B), which is overexpressed in AML. Overexpression of p200CUX1 downregulated BMP8B expression and inhibited the MAPK pathway. Furthermore, BMP8B knockdown inhibited AML cell proliferation, enhanced apoptosis and the sensitivity of ATRA-induced cell differentiation, and blocked G0/G1 transition. Our findings demonstrate the pivotal function of the p200CUX1-BMP8B-MAPK axis in maintaining the viability of AML cells. Consequently, targeting p200CUX1 could represent a viable strategy in AML therapy.

Targeting a lineage-specific PI3Kɣ-Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule.

Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ-PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models.

IRF2BP2 counteracts the ATF7/JDP2 AP-1 heterodimer to prevent inflammatory overactivation in acute myeloid leukemia (AML) cells.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of cell-intrinsic inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that IRF2BP2 interacts with the AP-1 heterodimer ATF7/JDP2, which is involved in activating inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene-activating function. Loss of IRF2BP2 leads to overactivation of inflammatory pathways, resulting in strongly reduced proliferation. Our research indicates that a precise equilibrium between activating and repressive transcriptional mechanisms creates a pro-oncogenic inflammatory environment in AML cells. The ATF7/JDP2-IRF2BP2 regulatory axis is likely a key regulator of this process and may, therefore, represent a promising therapeutic vulnerability for AML. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.

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

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

FYB1-targeted modulation of CAPG promotes AML progression.

Acute myeloid leukemia (AML) is a rare and heterogeneous disease. Over the past few decades, patient prognosis has improved with continuous improvements in treatment, but outcomes for some patients with primary drug resistance or relapse after treatment remain poor. Additional therapies to improve outcomes for these patients are urgently needed. FYB1 expression differs substantially between AML tissues and normal tissues. High FYB1 expression is correlated with poorer overall survival (OS), indicating that FYB1 may regulate AML progression. Therefore, understanding the effect of FYB1 on AML could improve the success rate of therapeutic approaches and prognosis for patients with AML. In this study, through analysis of large databases and both in vivo and in vitro experiments, we assessed the expression and role of FYB1 in AML and the relationship of FYB with patient prognosis. Downstream targets of the FYB1 gene were analyzed by RNA-seq. Database mining and in vitro experiments were used to further clarify the effect of the downstream target gelsolin-like actin-capping protein (CAPG) on AML cells and its relationship with patient prognosis. FYB1 expression was significantly higher in AML tissue and corresponded with a poor prognosis. FYB1 knockdown inhibited AML cell proliferation, promoted cell apoptosis, reduced cell adhesion capability and significantly reduced the tumor formation rate in mice. In addition, FYB1 knockdown induced a notable decrease in CAPG expression. The suppression of CAPG significantly inhibited cell proliferation and increased cell apoptosis. The conclusions of this study underscore the pivotal role of the FYB1/CAPG axis in promoting AML. We propose that the FYB1/CAPG axis could serve as a new thread in the development of therapeutic strategies for AML.

Emetine induces oxidative stress, cell differentiation and NF-κB inhibition, suppressing AML stem/progenitor cells

Acute myeloid leukemia (AML) is a fatal malignancy of the blood and bone marrow. Leukemic stem cells (LSCs) are a rare subset of leukemic cells that promote the development and progression of AML, and eradication of LSCs is critical for effective control of this disease. Emetine is an FDA-approved antiparasitic drug with antitumor properties; however, little is known about its potential against LSCs. Herein, we explored the antileukemic potential of emetine, focusing on its effects on AML stem/progenitor cells. Emetine exhibited potent cytotoxic activity both in hematologic and solid cancer cells and induced AML cell differentiation. Emetine also inhibited AML stem/progenitor cells, as evidenced by decreased expression of CD34, CD97, CD99, and CD123 in KG-1a cells, indicating anti-AML stem/progenitor cell activities. The administration of emetine at a dosage of 10 mg/kg for two weeks showed no significant toxicity and significantly reduced xenograft leukemic growth in vivo. NF-κB activation was reduced in emetine-treated KG-1a cells, as shown by reduced phospho-NF-κB p65 (S529) and nuclear NF-κB p65. DNA fragmentation, YO-PRO-1 staining, mitochondrial depolarization and increased levels of active caspase-3 and cleaved PARP (Asp214) were detected in emetine-treated KG-1a cells. Moreover, treatment with the pancaspase inhibitor Z-VAD(OMe)-FMK partially prevented the apoptotic cell death induced by emetine. Emetine treatment also increased cellular and mitochondrial reactive oxygen species, and emetine-induced apoptosis in KG-1a cells was partially prevented by the antioxidant N-acetylcysteine, indicating that emetine induces apoptosis, at least in part, by inducing oxidative stress. Overall, these studies indicate that emetine is a novel potential anti-AML agent with promising activity against stem/progenitor cells, encouraging the development of further studies aimed at its clinical application.

The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.

Adhesion GPCR ADGRE2 Maintains Proteostasis to Promote Progression in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematologic malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G protein-coupled receptors (GPCR) play integral roles in physiologic processes and human diseases. Particularly, one third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Here, we investigate the role of adhesion GPCRs in AML and whether they could be harnessed as antileukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells, which is associated with poor patient outcomes. Silencing ADGRE2 not only exerts antileukemic effects in AML cell lines and cells derived from patients with AML in vitro, but also delays AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activates phospholipase Cβ/protein kinase C/MEK/ERK signaling to enhance the expression of AP1 and transcriptionally drive the expression of DUSP1, a protein phosphatase. DUSP1 dephosphorylates Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitates the DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP1, and DUSP1 exhibits robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML. Significance: Increased expression of the adhesion GPCR member ADGRE2 in AML supports leukemia stem cell self-renewal and leukemogenesis by modulating proteostasis via an MEK/AP1/DUSP1 axis, which can be targeted to suppress AML progression.

Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression.

Acute myeloid leukaemia (AML) management remains a significant challenge in oncology due to its low survival rates and high post-treatment relapse rates, mainly attributed to treatment-resistant leukaemic stem cells (LSCs) residing in bone marrow (BM) niches. This review offers an in-depth analysis of AML progression, highlighting the pivotal role of extracellular vesicles (EVs) in the dynamic remodelling of BM niche intercellular communication. We explore recent advancements elucidating the mechanisms through which EVs facilitate complex crosstalk, effectively promoting AML hallmarks and drug resistance. Adopting a temporal view, we chart the evolving landscape of EV-mediated interactions within the AML niche, underscoring the transformative potential of these insights for therapeutic intervention. Furthermore, the review discusses the emerging understanding of endothelial cell subsets' impact across BM niches in shaping AML disease progression, adding another layer of complexity to the disease progression and treatment resistance. We highlight the potential of cutting-edge methodologies, such as organ-on-chip (OoC) and single-EV analysis technologies, to provide unprecedented insights into AML-niche interactions in a human setting. Leveraging accumulated insights into AML EV signalling to reconfigure BM niches and pioneer novel approaches to decipher the EV signalling networks that fuel AML within the human context could revolutionise the development of niche-targeted therapy for leukaemia eradication.