Acute myeloid leukemia (AML) is a complex and aggressive hematopoietic malignancy. Clinically, adriamycin is an important therapeutic drug. However, drug resistance often leads to refractory or relapse of patients after anthracycline-based treatment, and the prognosis is poor. Despite extensive research, the molecular mechanisms underlying adriamycin resistance in AML remain elusive. 4D label-free quantitative proteomics and untargeted metabolomics techniques were used to quantify and analyze the protein and metabolic profiles of HL60 and adriamycin-resistant cell line HL60/R. A total of 3,241 proteins were differentially expressed, including 1,686 up-regulated and 1,555 down-regulated proteins, and 260 metabolites were differentially expressed with 79 up-regulated and 41 down-regulated under positive ion mode, and 77 up-regulated and 63 down-regulated under negative ion mode in HL60/R compared to HL60. Subsequently, bioinformatics analysis of the altered proteins showed that they were involved in many biological processes, particularly cAMP signaling pathway, HIF-1 signaling pathway and oxidative phosphorylation. Furthermore, an integrated analysis of proteome and metabolome showed that the significantly altered metabolism pathways were mainly involved in amino acid metabolism, such as alanine, aspartate and glutamate metabolism, cysteine and methionine metabolism and glutathione metabolism, which indicated that they may participated in the pathogenesis of drug resistance in HL60 cells. Finally, six significantly changed proteins including GOT1, GPX1, AHCY, MAT2A, BCAT1, GCLM in amino acid metabolism were further validated through western blot. MAT2A, BCAT1 and GCLM were selected for small interfering RNA experiments and the results exhibited that apoptosis rates significantly promoted in HL60/R when MAT2A, BCAT1 or GCLM were interfered. An integrative analysis of proteomic and metabolomic data revealed significant disruptions in amino acid metabolism in HL60/R cells, including the metabolic pathways of alanine, aspartate and glutamate, cysteine and methionine, as well as glutathione metabolism.

Exploring the potential link between mRNA COVID-19 vaccinations and cancer: A case report with a review of haematopoietic malignancies with insights into pathogenic mechanisms

INTRODUCTION: Chronic Myeloid Leukaemia (CML) is a hematopoietic malignancy caused by the BCR-ABL1 fusion oncoprotein, originating from Philadelphia chromosome translocation that enhances leukemic cell survival and therapeutic resistance. Aberrant MAPK pathway activation promotes proliferation and inhibits apoptosis, contributing to CML progression and resistance to tyrosine kinase inhibitors like imatinib with prolonged use. Thymoquinone (TQ), a bioactive molecule, has attracted considerable interest Z for its anticancer characteristics that are worth investigating. MATERIALS AND METHODS: K562 CML cells were divided into an untreated group and a TQ-treated group and observed for 24 and 48 hours. Different TQ concentrations were administered to the TQ-treated group. Dose and time dependent effects on cell growth were assessed to evaluate cytotoxicity and determine the IC50 value in both groups. RNA was extracted from K562 CML cells based on the IC50 value and proceeded with RT-qPCR analysis on 7 genes involved, assigned as Raf1, B-Raf, ERK1, ERK2, K-Ras, H-Ras, and N-Ras genes, while the beta-actin gene was used as a housekeeping gene. Protein was extracted for the determination of protein and phosphorylation levels of Raf, MEK1/2, and ERK1/2, and assessed using the Jess Simple Western protocol. The Wilcoxon Signed-Rank test was performed using IBM SPSS, with p<0.05 considered statistically significant. Results: TQ treatment significantly reduced the expression of all genes analysed in K562 cells. It also decreased protein and phosphorylation levels of Raf, MEK1/2, and ERK1/2. Conclusion: These findings suggest that TQ effectively inhibits MAPK signalling in K562 CML cells, highlighting its potential as a future treatment for CML.

Integrated one-pot RPA-CRISPR/Cas13a platform enables ultrasensitive and field-deployable JAK2 V617F detection for myeloproliferative neoplasm diagnosis.

BACKGROUNDOur mission is to cure hematopoietic malignancies through cell therapy. Time to transplant is a key challenge resulting in mortality of patients needing a transplant. Previous studies reported CD146+ mesenchymal stem cells (MSCs) regulating hematopoiesis in bone marrow (BM). In 2013, the study reported the existence in the synovium of a MSC subset, co-expressing CD73 and CD39, with greater osteo-chondrogenic potency and ability to produce adenosine. This subset expressed CD146, known to be associated with pericytes.AIMTo investigate the presence and characterization of the CD73+CD39+CD146+ MSC subset in BM. Furthermore, we explored the existence of this subset in mobilized blood.METHODSBM cells were culture expanded up to passage 4. Flow cytometry was used to verify expression of CD73, CD39, and CD146 markers. Cell sorting was performed via BDFACS AriaTM Fusion. The subset was assessed for defined MSC characteristics and perivascular localization in BM sections. Peripheral blood derived MSCs were obtained through apheresis performed at Gift of Life under Institutional Review Board donor consent.RESULTSOur findings demonstrated that the combination of CD73, CD39, and CD146 enabled the identification and purification of a subset of MSCs from culture-expanded BM, up to passage 4. This subset exhibited a CD45-CD73+CD39+CD146+ phenotype, along with self-renewal and multipotency abilities, and was located in perivascular areas of BM sections. Additionally, this subset was found in both single and dual-mobilized leukopaks.CONCLUSIONThe CD73+CD39+CD146+ cell subset showed self-renewal and multipotency abilities and was located in perivascular areas of BM. Such cell subset was also reported in single and dual-mobilized leukopaks.

Canine lymphoma comprises the majority of haematopoietic malignancies in veterinary clinical practice. Several prognostic factors have been studied and, more recently, there has been an increased interest in the role of the lymphocyte-to-monocyte ratio (LMR) for its prognostic value. To date, the prognostic value of absolute monocyte and lymphocyte counts as well as LMR at the time of relapse in dogs with diffuse large B-cell lymphoma has not been evaluated. The purpose of the present study was to investigate whether the absolute monocyte, lymphocyte or LMR at relapse can predict clinical outcomes for relapsed diffuse large B-cell lymphoma dogs treated with chemotherapy. Additionally, the parameters were evaluated for their prognostic value at the time of diagnosis and throughout different timepoints during the course of their first-line chemotherapy treatment. We retrospectively analysed data from 50 dogs with relapsed diffuse large B-cell lymphoma, treated with a CEOP-based first-line chemotherapy protocol. Lymphocyte and monocyte count and LMR were evaluated at different timepoints: at diagnosis, during chemotherapy and at the time of relapse. Overall survival time (OS) and disease-free interval (DFI), as well as overall survival time from relapse (OSr), were measured. Friedman nonparametric ANOVA was used to compare blood cell counts at different timepoints. Spearman rank correlation was used to test for association between blood cell count at various timepoints with the duration of remission and survival time. Monocyte and lymphocyte counts and LMR at the time of first relapse were not found to be adverse prognostic factors for OSr in this population of dogs. Monocyte and lymphocyte counts differed significantly between different timepoints during the chemotherapy protocol. Absolute monocyte and lymphocyte counts and LMR at the time of relapse were not found to be prognostic indicators of OSr in this population of dogs with multicentric lymphoma. Additional studies evaluating absolute monocyte and lymphocyte counts during chemotherapy treatment and following completion of chemotherapy in larger population of dogs are needed to assess whether these counts have clinical utility in detecting disease progression.

Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.

Abstract Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy characterized by differentiation arrest of immature myeloid cells. Although all‐trans retinoic acid therapy benefits patients with AML subtype acute promyelocytic leukemia, some subtypes of patients are not responsive, raising the need to explore alternative therapeutical options. In this study, we report that Solamargine (SM), a steroidal alkaloid glycoside isolated from the Chinese herb Solanum nigrum L., shows promising anti‐AML activities. SM inhibits the cellular growth and promotes the apoptosis of AML cells. In particular, we demonstrate that SM induces AML differentiation by Toll‐like receptor 8 (TLR8) activation. These findings indicate that SM exerts an anti‐AML effect, at least in part, by activating TLR8. Our work also suggests SM as a potential therapeutic compound for treating AML.

Although Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable success in treating hematopoietic malignancies, its clinical application in solid tumors is profoundly hindered by persistent T-cell exhaustion within the immunosuppressive tumor microenvironment (TME). Here, we identified SATB1-a genome organizer regulating chromatin architecture-as a key suppressor of CAR-T cell exhaustion. In Glypican-3 (GPC3)-targeted CAR-T cells, SATB1 was significantly downregulated in tumor-infiltrating exhausted populations. SATB1 overexpression not only reduced expression of multiple inhibitory receptors (PD-1, CTLA-4, TIM3, and LAG-3) but also promoted a central memory phenotype, enhancing cytokine production and cytotoxicity against hepatocellular carcinoma (HCC) cells in vitro. In vivo, SATB1-engineered CAR-T cells exhibited superior tumor control and promoted survival, accompanied by reduced exhaustion markers in tumor-infiltrating T cells. These functional improvements are consistent with the reported role of SATB1 in modulating T cell exhaustion, positioning it as a multifunctional enhancer of CAR-T cell fitness. Collectively, our study unveils SATB1 as a multifunctional modulator that simultaneously targets exhaustion and memory differentiation, offering a novel strategy to enhance CAR-T efficacy against solid tumors.

Abstract INTRODUCTION Myeloproliferative Neoplasms (MPN) are a group of hematopoietic malignancies generally seen in older adults, but more cases are being diagnosed in younger patients (ranging from 0 to ∼30 years) for whom the etiology is poorly understood. Assessing early-life exposures and their potential effects on the biology of the individual is complex. However dried blood spots (DBS) which are collected at birth, years preceding the development of cancer, provide a resource to retrospectively analyze this critical window of exposure. Metabolomics analysis of these DBS offer a unique opportunity to measure both exposures and biological effect, through the examination of metabolites, including those derived from environmental sources, the microbiome, and endogenous processes. MATERIAL AND METHOD This study investigates the role of early-life exposures in the pathogenesis of early-onset MPN (EO-MPN) through untargeted metabolomics-based mass spectrometry on neonatal DBS samples. We combine a broad analysis of cases versus matched controls with a focused investigation of cohort-specific factors within the cases. This multi-step approach allows for the identification of potential confounding factors related to the general population and isolates those that are likely to contribute to the disease. RESULT AND DISCUSSION Multivariate statistical analyses such as PCA, PLS-DA and Uniform Manifold Approximation and Projection (UMAP), revealed subtle metabolic differences between cases and control particularly when stratifying by age of diagnosis and birth cohort. Despite the modest fold changes resulting from the comparison, key metabolic alterations in the cases were measured for fatty acids, amino acids and metabolites involved in redox pathways. CONCLUSION This study represents the first application of a comprehensive metabolomics analysis in the context of early-onset MPN. The findings from this preliminary analysis suggest that early life metabolic shifts may play a role in MPN development, and lay the groundwork for future research to explore these metabolites as potential biomarkers and therapeutic targets for EO-MPN. Citation Format: Domenica Berardi. Neonatal Dried Blood Spot Metabolomics Reveals Signatures of Early-Onset Myeloproliferative Neoplasms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr C003.

Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor gene, and loss or dysregulation thereof plays a central role in leukemogenesis processes, disease progression, and resistance to anticancer therapy in myeloid and lymphoid leukemias. Growing research highlights the complex regulatory landscape involving noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), providing overwhelming evidence that supports the critical role of these molecules in regulating PTEN expression and functionality in leukemia scenarios. The therapeutic potential of regulating PTEN through ncRNAs reveals selective targets that potentially break anticancer resistance and enhance patient outcomes. A host of ncRNAs holds promise as potential diagnostic and prognostic markers for leukemia. A critical analysis of the complex interactions that explain the various roles of the ncRNAs in the regulatory landscape surrounding PTEN can form the basis for developing RNA-targeted new therapeutic strategies aimed at hematopoietic malignancies. The review aims to provide a thorough and critical evaluation of the regulatory influence of ncRNAs on the expression and functionality of PTEN in myeloid and lymphoid leukemias. Focusing on the molecular mechanisms that facilitate modulation by various classes of RNAs (miRNAs, lncRNAs, circRNAs), we aim to bring into sharper focus the contributions of these RNAs to leukemic progression and therapeutic response, as well as provide valuable insights into potential targets and markers for the development of innovative therapeutic approaches.

Novel strategy for overcoming interference from anti-CD47 agents in pretransfusion testing.

Acute myeloid leukemia (AML) is a lethal clonal hematopoietic malignancy. Several reports have shown that serum metabolite alterations have been implicated in AML, but the causal relationship and underlying biological mechanisms remain unclear. We performed bidirectional Mendelian randomization (MR) to evaluate the association between 486 serum metabolites and AML. The analytical approaches used to minimize research bias included the inverse variance weighting (IVW), MR-Egger and weighted median (WM) methods. Sensitivity analyses were performed using Cochran’s Q Test, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and Leave-one-out (LOO) analysis. Metabolic pathway analysis was conducted using the MetaboAnalyst 6.0 platform. We utilized RNA-seq data to explore the potential genes and mechanisms underlying the regulation of AML occurrence by serum metabolites. We identified 23 serum metabolites (13 known and 10 unknown) significantly associated with AML. Sensitivity analyses further validated the robustness of these associations. No evidence of reverse causality was detected by reverse MR analysis. The core pathways were histidine metabolism and fructose/mannose metabolism. Transcriptomic integration revealed 39 overlapping genes (differentially expressed genes vs. metabolite-associated genes) as key mediators, enriched in neuroactive ligand signaling, synaptic vesicle cycle, and GABAergic synapse (KEGG), plus synapse assembly and calmodulin binding and neuron-to-neuron synapse (GO). This study establishes causal links between specific serum metabolites and AML, revealing neuro-related mechanistic pathways. These findings provide novel biomarkers and therapeutic targets for AML precision medicine.

Canine lymphoma is a common hematopoietic malignancy with limited therapeutic options, particularly in drug-resistant cases. Overexpression of Exportin 1 (XPO1) promotes oncogenesis by impairing the nuclear-cytoplasmic translocation of tumor suppressor proteins (TSPs). KPT-335 (Verdinexor), a selective XPO1 inhibitor, restores TSP function, inducing cell cycle arrest and apoptosis. In this study, we investigated the in vitro effects of KPT-335 alone and in combination with doxorubicin or vincristine in four canine lymphoma cell lines. KPT-335 reduced XPO1 protein expression in a dose-dependent manner, an effect reversed by proteasome inhibition, suggesting proteasome-mediated degradation. Combination treatments significantly suppressed cell proliferation compared with single agents. These findings highlight the preclinical evidence of combining KPT-335 with conventional chemotherapies in canine lymphoma.

To describe cause-specific mortality patterns of banana plantation workers in the French West Indies. The study included 11 221 farmers and farm workers who had work in banana cultivation in the French West Indies (Guadeloupe or Martinique) between 1973 and 1993, followed up from January 1981 to December 2017. We calculated standardised mortality ratios (SMRs), causal mortality ratios (CMRs) and relative standardised mortality ratios (rSMRs) using regional reference rates. SMR analyses showed mortality deficits in the overall mortality and for almost all causes of deaths. In contrast, analyses using CMRs revealed a significant excess in the overall mortality. The CMRs were significantly elevated for all cancers combined and for stomach cancer, colorectal cancer, prostate cancer and haematopoietic malignancies, as well as for several non-cancer causes of death, including diabetes mellitus, Parkinson's disease, Alzheimer's disease, non-ischaemic heart diseases, pneumonia and diseases of the skin and subcutaneous tissue. rSMRs were in general consistent with CMRs with regards to the direction of the association, although rSMRs were lower and in some instances not statistically significant. The CMR approach showed an elevated mortality for several causes of death, for which work in banana farming and/or exposure to pesticides are plausible explanations.

The maintenance of a basal immunoinflammatory signature in hematopoietic stem/progenitor cells (HSPCs) constitutes a fundamental regulatory axis governing hematopoietic competence and immune effector generation. While epigenetic repressors constrain this inflammatory phenotype, the molecular amplifiers that preserve this critical state remain undefined. Through integrated single-cell transcriptomic/epigenomic profiling and functional interrogation, we identify Setd2-mediated H3K36me3 as an indispensable epigenetic amplifier sustaining baseline inflammation in murine HSPCs. Setd2 ablation specifically eliminated interferon (IFN)-enriched HSPC subpopulations and attenuated inflammatory signaling cascades. Functionally, Setd2-deficient HSPCs exhibited impaired IFNγ responsiveness, compromised B-lymphopoiesis, and diminished reconstitution capacity due to Lin−c-Kit+Sca1high cell depletion. Paradoxically, Setd2 loss conferred resistance to IFNγ-induced HSPCs exhaustion, which may contribute to the maintenance of Setd2-deficient HSPCs in our myelodysplastic syndrome (MDS) model under the inflammatory milieu. Mechanistically, Setd2 sustained chromatin accessibility and enhancer (H3K27ac) activity at inflammatory gene loci. This work delineates a critical link between Setd2-mediated chromatin regulation, baseline inflammation, HSPC function, and immune competence, providing insights into inflammatory dysregulation in hematopoietic malignancies like MDS.

Title: Hacs1 is a myeloma immunosuppressor driving pro-tumorigenic myelopoiesis and myeloid cell differentiation through MS4A3/IL3/GM-CSF signaling

Feasibility and tolerability of a CD4 re-directed chimeric antigen receptor T cell therapy (CD4CAR) in hematologic malignancies: Initial Results from multi-institutional first-in-human trials

CRISPR-tica.ai: A function-informed generative modeling pipeline for prioritizing drug discovery in AML

CpG-level DNA methylation analysis identifies molecular events that are definitive of progressive lineage commitment in hematopoiesis