Metabolomic insights into pathogenesis and therapeutic potential in adult acute lymphoblastic leukemia

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(7)

Опубликована: Фев. 13, 2025

Acute lymphoblastic leukemia (ALL) poses challenges in adult patients, considering its heterogeneous nature and often suboptimal treatment outcomes. Here, we performed a study on 201 newly diagnosed ALL cases (age ≥ 15 y) to generate intracellular dynamic serum metabolomic profiles. Our findings revealed predominant increase bile acid (BA) metabolites serum, alongside metabolic rewiring that supported highly proliferative states actively signaling, such as enriched nucleotide metabolism leukemic blasts. By integrating metabolomics transcriptomics, constructed the Comprehensive Metabolic Information Dataset (CMID), which facilitated development of clustering system supplement current risk stratification. Furthermore, explored potential interventions targeting BA profile energy The combined use simvastatin with vincristine dexamethasone regimen demonstrated synergistic therapeutic effect murine model, effectively lowering key levels suppressing infiltration blasts liver. In light enhanced redox metabolism, combining FK866 (a nicotinamide phosphoribosyltransferase inhibitor) venetoclax significantly prolonged survival patient-derived xenograft model. findings, along resulting resources ( http://www.genetictargets.com/MALL ), provide framework for metabolism-centered management ALL.

Язык: Английский

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Prediction of survival in acute myeloid leukemia patients by extracellular to intracellular water ratio and sarcopenia: development and validation of a novel nomogram

Annals of Hematology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 18, 2025

Acute myeloid leukemia (AML) commonly affects the elderly with a poor prognosis. Body water composition analysis provides new perspective for biomedical research. This study aims to develop and validate simple nomogram predicting overall survival (OS) in AML survivors. A total of 291patients were enrolled randomly divided into training cohort an internal validation cohort. The median duration follow-up was 32.2 months.The LASSO regression used screen predictors cohort, multivariate Cox model establish nomogram. discrimination calibration evaluated using C-index, area under time-dependent receiver operating characteristic curve (time-dependent AUC), plots. net benefits at different threshold probabilities quantified. Five identified: Age, Extracellular water/Intracellular (ECW/ICW) ratio, European Leukemia Net Risk, Sarcopenia, WBC. showed good performance both (C-index 0.755, 95% CI 0.728–0.782) 0.773, 0.729 0.817). AUC values 0.866, 0.849, 0.818, 0.779 12, 24, 36, 48 months, respectively; 0.799, 0.779, 0.797, 0.786 respectively. curves acceptable consistency, decision indicated higher benefit clinical practice. In this study, we developed validated easily applicable predict OS patients.

Язык: Английский

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Clonal hematopoiesis, cardiovascular disease and cancer treatment-induced cardiotoxicity

Seminars in Cancer Biology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Implications of Clonal Hematopoiesis in Hematological and Non-Hematological Disorders

Cancers, Год журнала: 2024, Номер 16(23), С. 4118 - 4118

Опубликована: Дек. 9, 2024

Clonal hematopoiesis (CH) is associated with an increased risk of developing myeloid neoplasms (MNs) such as myelodysplastic neoplasm (MDS) and acute leukemia (AML). In general, CH comprises clonal indeterminate potential (CHIP) cytopenia undetermined significance (CCUS). It age-related phenomenon characterized by the presence somatic mutations in hematopoietic stem cells (HSCs) progenitor (HSPCs) that acquire a fitness advantage under selection pressure. Individuals CHIP have absolute 0.5-1.0% per year for progressing to MDS or AML. Inflammation, smoking, cytotoxic therapy, radiation can promote process expansion leukemic transformation. Of note, exposure chemotherapy patients solid tumors lymphomas increase therapy-related MN. Beyond hematological malignancies, also serves independent factor heart disease, stroke, chronic obstructive pulmonary kidney disease. Prognostic models score MN-prediction provide framework stratification clinical management CHIP/CCUS identify high-risk individuals who may benefit from close surveillance. For related disorders, therapeutic strategies targeting specific CH-associated pressure role future.

Язык: Английский

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Acute myeloid leukemia risk stratification in younger and older patients through transcriptomic machine learning models

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 13, 2024

ABSTRACT Acute Myeloid Leukemia (AML) is a heterogeneous disease that may occur at any age. Although it has been shown the incidence of AML increases with age and different genetic alterations are present in younger versus older patients, current classifications do not include as factor classifying patients. In this work, we analyzed 404 RNA-seq samples initial diagnosis to highlight differences between patients favorable adverse risk using k-mer-based approach for transcriptomic machine learning models. We predicted more than 90% accuracy. also provided lists genes interest were able distinguish from ELN risks. From these lists, selected prognostic biomarkers have an impact on survival. Furthermore, biological context involved transcriptome complexity observed tumor profiles well presence immune stromal cell populations specific features

Язык: Английский

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ADAR1 is required for acute myeloid leukemia cell survival by modulating post-transcriptional Wnt signaling through impairing miRNA biogenesis

Leukemia, Год журнала: 2024, Номер unknown

Опубликована: Дек. 19, 2024

Язык: Английский

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