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Mediation analysis for TNF-α as a mediator between multiple metal exposure and kidney function

Ecotoxicology and environmental safety 2024年 283卷 116837页

作者： Kuei-Hau Luo Hung-Pin Tu Huang-Chih Chang Chen-Cheng Yang Wei-Chun Weng Tzu-Hua Chen Cheng-Hong Yang Hung-Yi Chuang Graduate Institute of Medicine College of Medicine Kaohsiung Medicine University Kaohsiung City 807 Taiwan. Department of Public Health and Environmental Medicine School of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 807 Taiwan. Divisions of Pulmonary & Critical Care Medicine Department of Internal Medicine Kaohsiung Chang Gung Memorial Hospital Chang Gung University College of Medicine Kaohsiung Taiwan. Graduate Institute of Medicine College of Medicine Kaohsiung Medicine University Kaohsiung City 807 Taiwan Department of Occupational Medicine Kaohsiung Municipal Siaogang Hospital Kaohsiung Medical University Kaohsiung 812 Taiwan. Division of Gastroenterology Department of Internal Medicine Kaohsiung Armed Forces General Hospital Kaohsiung 802 Taiwan. Department of Family Medicine Kaohsiung Municipal Ta-Tung Hospital Kaohsiung 801 Taiwan. Department of Information Management Tainan University of Technology Tainan 71002 Taiwan Department of Electronic Engineering National Kaohsiung University of Science and Technology Kaohsiung 80778 Taiwan. Department of Public Health and Environmental Medicine School of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 807 Taiwan Department of Occupational and Environmental Medicine Kaohsiung Medicine University Hospital Kaohsiung Medicine University Kaohsiung 807 Taiwan Ph.D. Program in Environmental and Occupational Medicine College of Medicine and Research Center for Precision Environmental Medicine Kaohsiung Medical University Kaohsiung 807 Taiwan. Electronic address: ericch@kmu.edu.tw.

The association between metal mixtures and kidney function has been reported. However, reports on the mechanism of metal toxicity were limited. Oxidative stress was reported as a possible cause. This study aimed to determine the association between of kidney function and metals, such as arsenic (As), cadmium (Cd), cobalt (Co), copper (Cu), lead (Pb), selenium (Se), and zinc (Zn), and to explore the possible mediating role of tumor necrosis factor alpha (TNF-α) between metal toxicity and kidney function. In this study, we recruited 421 adults from a health examination. The concentration of blood metals was analyzed using inductively coupled plasma mass spectrometry. We used linear regression models to assess the association between metals and TNF-α. Then, mediation analysis was applied to investigate the relationship between metal exposure, TNF-α, and kidney function. In univariate linear regression, blood As, Cd, Co, Cu, Pb, and Zn levels significantly increased TNF-α and decreased kidney function. Higher blood As and Pb levels significantly increased TNF-α in multivariable linear regressions after adjusting for covariates. We found that blood levels of As (coefficients = -0.021, p = 0.011), Pb (coefficients = -0.060, p < 0.001), and Zn (coefficients = -0.230, p < 0.001) showed a significant negative association with eGFR in the multiple-metal model. Furthermore, mediation analysis showed that TNF-α mediated 41.7 %, 38.8 %, and 20.8 % of blood Cd, As and Pb, respectively. Among the essential elements, TNF-α mediated 24.5 %, 21.5 % and 19.9 % in the effects of blood Co, Cu, and Zn on kidney function, respectively. TNF-α, acting as a mediator, accounted for 20.1 % of the contribution between the WQS score of metal mixtures and the eGFR (p < 0.001). This study suggested that TNF-α may be a persuasive pathway mediating the association between metals and kidney function. Inflammation and kidney injury could be the underlying mechanisms of metal exposure. However, there i

关键词： Kidney function Mediation analysis Metals Pb TNF-α

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A first-principles study on the quantum tunneling of methylhydroxycarbene isomerization in various solvents

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Journal of Physics: Conference Series 2020年第1期1568卷 012003-012003页

作者： E D Susanti F Rusydi I Puspitasari R N Fadilla N D Aisyah A Ahmad Research Center for Quantum Engineering Design Faculty of Science and Technology Universitas Airlangga Jl. Mulyorejo Surabaya 60115 Indonesia Department of Physics Faculty of Science and Technology Universitas Airlangga Jl. Mulyorejo Surabaya 60115 Indonesia Visiting Researcher at Precision Sciences & Technology and Applied Physics Graduate School of Engineering Osaka University Suita 565-0871 Japan Information System Study Program Faculty of Science and Technology Universitas Airlangga Jl. Mulyorejo Surabaya 60115 Indonesia School of Chemical Science and Food Technology Faculty of Science and Technology Universiti Kebangsaan Malaysia Bangi Selangor 43600 Malaysia

Quantum tunneling phenomenon allows a high-barrier reaction to occur even though thermal energy is not sufficient to surmount the barrier. The phenomenon has been suggested to exist in the isomerization of methylhydroxycarbene which occured at 11 K. Here we study the quantum tunneling that occured in the isomerization of methylhydroxycarbene to acetaldehyde and to vinyl alcohol based on density functional calculations. The isomerization pathways are determined under the effect of various solvents which are modeled by polarizable continuum model (PCM). We use Wentzel-Kramers-Brillouin (WKB) approximation to calculate the tunneling probability (T) and extend the usefulness of T into isomerization rate. The results show that the solvents give a significant effect on the isomerization rate of methylhydroxycarbene to acetaldehyde but an insignificant one on the isomerization rate to vinyl alcohol.

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Retraction notice to "Aptamer/doxorubicin-conjugated nanoparticles target membranous CEMIP2 in colorectal cancer" [International Journal of Biological Macromolecules 245 (2023) 125510]

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International journal of biological macromolecules 2025年 293卷 138914页

作者： Maryam Kianpour Ching-Wen Huang Pichpisith Pierre Vejvisithsakul Jaw-Yuan Wang L Chien-Feng Meng-Shin Shiao Cheng-Tang Pan Yow-Ling Shiue Institute of Biomedical Sciences College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan. Division of Colorectal Surgery Department of Surgery Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 80756 Taiwan Department of Surgery Faculty of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan. Institute of Biomedical Sciences College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan Program in Translational Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok 10400 Thailand. Department of Surgery Faculty of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan Pingtung Hospital Ministry of Health and Welfare Pingtung 900214 Taiwan Graduate Institute of Clinical Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan Graduate Institute of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan Center for Cancer Research Kaohsiung Medical University Kaohsiung 80756 Taiwan. Department of Medical Research Chi Mei Medical Center Tainan 71004 Taiwan Department of Pathology Chi Mei Medical Center Tainan 71004 Taiwan National Institute of Cancer Research National Health Research Institutes Tainan 70456 Taiwan. Research Center Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok 10400 Thailand. Institute of Precision Medicine College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan Department of Mechanical and Electro-Mechanical Engineering National Sun Yat-sen University Kaohsiung 80424 Taiwan.

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Retraction notice to "Corrigendum to 'Aptamer/doxorubicin-conjugated nanoparticles target membranous CEMIP2 in colorectal cancer' [International Journal of Biological Macromolecules 248 (2023) 125782]"

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International journal of biological macromolecules 2025年 293卷 138913页

作者： Maryam Kianpour Ching-Wen Huang Pichpisith Pierre Vejvisithsakul Jaw-Yuan Wang Chien-Feng Li Meng-Shin Shiao Cheng-Tang Pan Yow-Ling Shiue Institute of Biomedical Sciences College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan. Division of Colorectal Surgery Department of Surgery Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 80756 Taiwan Department of Surgery Faculty of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan. Institute of Biomedical Sciences College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan Program in Translational Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok 10400 Thailand. Department of Surgery Faculty of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan Pingtung Hospital Ministry of Health and Welfare Pingtung 900214 Taiwan Graduate Institute of Clinical Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan Graduate Institute of Medicine College of Medicine Medical University Kaohsiung 80756 Taiwan Center for Cancer Research Kaohsiung Medical University Kaohsiung 80756 Taiwan. Department of Medical Research Chi Mei Medical Center Tainan 71004 Taiwan Department of Pathology Chi Mei Medical Center Tainan 71004 Taiwan National Institute of Cancer Research National Health Research Institutes Tainan 70456 Taiwan. Research Center Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok 10400 Thailand. Institute of Precision Medicine College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan Department of Mechanical and Electro-Mechanical Engineering National Sun Yat-sen University Kaohsiung 80424 Taiwan.

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Serum and CSF metabolomics analysis shows Mediterranean Ketogenic Diet mitigates risk factors of Alzheimer's disease

npj metabolic health and disease

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npj metabolic health and disease 2024年第1期2卷 15页

作者： Annalise Schweickart Richa Batra Bryan J Neth Cameron Martino Liat Shenhav Anru R Zhang Pixu Shi Naama Karu Kevin Huynh Peter J Meikle Leyla Schimmel Amanda Hazel Dilmore Kaj Blennow Henrik Zetterberg Colette Blach Pieter C Dorrestein Rob Knight Suzanne Craft Rima Kaddurah-Daouk Jan Krumsiek Tri-Institutional Program in Computational Biology & Medicine Weill Cornell Medicine New York NY USA. Department of Physiology and Biophysics Weill Cornell Medicine Institute for Computational Biomedicine Englander Institute for Precision Medicine New York NY USA. Department of Neurology Mayo Clinic Rochester MN USA. Department of Pediatrics University of California San Diego La Jolla CA USA. Department of Microbiology New York University Grossman School of Medicine New York NY USA. Department of Biostatistics and Bioinformatics Duke University Durham NC USA. Tasmanian Independent Metabolomics and Analytical Chemistry Solutions (TIMACS) Hobart TAS Australia. Baker Heart and Diabetes Institute 75 Commercial Road Melbourne VIC Australia. Baker Department of Cardiovascular Research Translation and Implementation La Trobe University Bundoora VIC Australia. Department of Psychiatry and Behavioral Sciences Duke University Durham NC USA. Department of Psychiatry and Neurochemistry University of Gothenburg Gothenburg Sweden. Duke Molecular Physiology Institute Duke University Durham NC USA. Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego La Jolla CA USA. Departments of Pediatrics Computer Science and Engineering Bioengineering University of California San Diego La Jolla CA USA. Department of Gerontology and Geriatric Medicine Wake Forest University School of Medicine Winston Salem NC USA. Duke Institute of Brain Sciences Duke University Durham NC USA. Department of Medicine Duke University Durham NC USA.

Alzheimer's disease (AD) is influenced by a variety of modifiable risk factors, including a person's dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD's metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.

关键词： Diseases Metabolomics

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Author Correction: T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control

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Nature immunology 2023年第4期24卷 729页

作者： Maria M Steele Abhinav Jaiswal Ines Delclaux Ian D Dryg Dhaarini Murugan Julia Femel Sunny Son Haley du Bois Cameron Hill Sancy A Leachman Young H Chang Lisa M Coussens Niroshana Anandasabapathy Amanda W Lund Ronald O. Perelman Department of Dermatology NYU Grossman School of Medicine New York University Langone Health New York NY USA. Department of Cell Developmental and Cancer Biology and Knight Cancer Institute Oregon Health and Science University Portland OR USA. Department of Dermatology Microbiology and Immunology Meyer Cancer Center Englander Institute of Precision Medicine Weill Cornell Medicine New York NY USA. Applied Bioinformatics Laboratories NYU Langone Health New York NY USA. Department of Dermatology Oregon Health and Science University Portland OR USA. Department of Biomedical Engineering and Computational Biology Program Oregon Health and Science University Portland OR USA. OHSU Center for Spatial Systems Biomedicine Oregon Health and Science University Portland OR USA. Ronald O. Perelman Department of Dermatology NYU Grossman School of Medicine New York University Langone Health New York NY USA. amanda.lund@***. Department of Cell Developmental and Cancer Biology and Knight Cancer Institute Oregon Health and Science University Portland OR USA. amanda.lund@***. Department of Pathology NYU Grossman School of Medicine New York University Langone Health New York NY USA. amanda.lund@***. Laura and Isaac Perlmutter Cancer Center NYU Grossman School of Medicine New York University Langone Health New York NY USA. amanda.lund@***.

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Cytopenias and Failure to Use Innovative Therapy Are Main Drivers of Worse Outcome after Discontinuation of Ruxolitinib in Myelofibrosis

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Blood 2024年 144卷 6664-6664页

作者： Francesca Palandri Massimo Breccia Erika Morsia Giulia Benevolo Mario Tiribelli Eloise Beggiato Mirko Farina Bruno Martino Giovanni Caocci Novella Pugliese Alessia Tieghi Monica Crugnola Gianni Binotto Francesco Cavazzini Elisabetta Abruzzese Alessandro Isidori Alessandra Dedola Emilia Scalzulli Alessia Moioli Veronica Guglielmana Filippo Branzanti IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi Istituto di Ematologia “Seràgnoli” Bologna Italy Department of Translational and Precision Medicine Az. Policlinico Umberto I-Sapienza University Rome Italy Hematology Unit Department of Clinical and Molecular Sciences Università Politecnica delle Marche Ancona Ancona Italy Division of Hematology 1 Department of Biotechnology and Health Sciences University of Torino Torino Italy Division of Hematology and BMT Department of Medical Area University of Udine Udine Italy Hematology AOU Città della Salute e della Scienza di Torino-Presidio Ospedaliero Molinette Turin Italy Unit of Blood Diseases and Bone Marrow Transplantation Cell Therapies and Hematology Research Program Department of Clinical and Experimental Science University of Brescia ASST Spedali Civili di Brescia University of Brescia ASST Spedali Civili Brescia Italy Division of Hematology Azienda Ospedaliera ‘Bianchi Melacrino Morelli’ Reggio Calabria Italy Department of Medical Sciences and Public Health University of Cagliari Cagliari Italy 10) Department of Clinical Medicine and Surgery Federico II University Medical School Naples Italy Napoli ITA Department of Hematology Azienda USL - IRCCS di Reggio Emilia Reggio Emilia Italy Hematology Unit and BMT Center Azienda Ospedaliero Universitaria Parma Parma Italy Department of Medicine Hematology and Clinical Immunology University of Padua Padua Italy Division of Hematology Arcispedale Sant'Anna University of Ferrara Ferrara ITA Department of Hematology S. Eugenio Hospital Tor Vergata University ASL Roma 2 Roma Italy Hematology and Stem Cell Transplant Center AORMN Hospital Pesaro Italy IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli” Bologna Bologna Italy Dipartimento di Medicina Specialistica Diagnostica e Sperimentale Università di Bologna Bologna Bologna Italy Hematology Department of Translational and Precision Me

Introduction Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by marrow fibrosis, and progressive splenomegaly, symptoms and cytopenias. Ruxolitinib (RUX) is a JAK1/2 inhibitor that can reduce spleen size and symptom burden and improve overall survival (OS). However, the prognosis after RUX discontinuation is poor, particularly in patients (pts) with clonal evolution and/or leukemic transformation (LT) ( Newberry et al, Blood 2017 ). Limited data are available on clinical outcomes of pts discontinuing RUX while in chronic phase. Aims To evaluate the outcomes after RUX discontinuation of chronic phase MF pts, focusing on the impact of disease phenotype and subsequent treatment strategies on OS. Methods After IRB approval (approval file number: 048/2022/Oss/AOUBo), the “RUX-MF” retrospective multicenter study collected 1055 MF pts who received RUX outside clinical trials. Survival analyses were performed using Kaplan-Meier curves, and differences were evaluated using the log-rank test. OS was calculated from the date of ruxolitinib discontinuation to death, allogeneic transplant (ASCT), last contact or from the date of 2nd line therapy start, to either death, or last contact. Cox regression models and delay entry were used to perform estimated survival plots. Results Among 1055 pts included in the RUX-MF study, 718 (68.1%) pts discontinued RUX; 397 pts were alive and in chronic phase at RUX discontinuation and were included in this analysis. Median OS of these 397 pts from RUX stop was 27.6 months (1.2 - 181.2). At RUX discontinuation, 208 (52.4%) pts had a cytopenic phenotype, including 122 pts with only platelet (PLT) ≤100 x10 9 /L, 35 pts with only hemoglobin (Hb) ≤8 g/dL, and 51 pts having both low PLT and Hb values. Among the remaining 189 pts, 55 had a fully proliferative phenotype (Hb>10 g/dL, PLT>100 x10 9 /L and spleen palpable ≥5 cm below costal margin, BCM) and 134 had a mild anemia (Hb between 8 and 10 g/dL) with or without palpabl

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Corrigendum to: "Aptamer/doxorubicin-conjugated nanoparticles target membranous CEMIP2 in colorectal cancer" [Int. J. Biol Macromol. 245 (2023) Jun 21;125510/Online ahead of print. PMID: 37353120;IJBIOMAC-D-23-03903R1]

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International journal of biological macromolecules 2023年 248卷 125782页

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Aptamer/doxorubicin-conjugated nanoparticles target membranous CEMIP2 in colorectal cancer

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International journal of biological macromolecules 2023年 245卷 125510页

作者： Maryam Kianpour Ching-Wen Huang Pichpisith Pierre Vejvisithsakul Jaw-Yuan Wang Chien-Feng Li Meng-Shin Shiao Cheng-Tang Pan Yow-Ling Shiue Institute of Biomedical Sciences College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan. Division of Colorectal Surgery Department of Surgery Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung 80756 Taiwan Department of Surgery Faculty of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan. Institute of Biomedical Sciences College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan Program in Translational Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok 10400 Thailand. Department of Surgery Faculty of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan Pingtung Hospital Ministry of Health and Welfare Pingtung 900214 Taiwan Graduate Institute of Clinical Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan Graduate Institute of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 80756 Taiwan Center for Cancer Research Kaohsiung Medical University Kaohsiung 80756 Taiwan. Department of Medical Research Chi Mei Medical Center Tainan 71004 Taiwan Department of Pathology Chi Mei Medical Center Tainan 71004 Taiwan National Institute of Cancer Research National Health Research Institutes Tainan 70456 Taiwan. Research Center Faculty of Medicine Ramathibodi Hospital Mahidol University Bangkok 10400 Thailand. Institute of Precision Medicine College of Medicine National Sun Yat-sen University Kaohsiung 80424 Taiwan Department of Mechanical and Electro-Mechanical Engineering National Sun Yat-sen University Kaohsiung 80424 Taiwan. Electronic address: pan@mem.nsysu.edu.tw. Department of Mechanical and Electro-Mechanical Engineering National Sun Yat-sen University Kaohsiung 80424 Taiwan. Electronic address: shirley@imst.nsysu.edu.tw.

The objectives were to identify the functional domains of a potential oncoprotein, cell migration inducing hyaluronidase 2 (CEMIP2), evaluate its expression levels and roles in colorectal cancer (CRC), and develop an aptamer-based nanoparticle for targeted therapy. Data mining on TCGA identified that CEMIP2 might play oncogenic roles in CRC. In a local cohort, CEMIP2 mRNA levels significantly stepwise increase in CRC patients with higher stages, and high CEMIP2 confers worse disease-free survival. In addition, CEMIP2 mRNA levels significantly correlated to hyaluronan levels in sera from CRC patients. Deletion mapping identified that CEMIP2 containing G8 and PANDER-like domains preserved hyaluronidase activity and oncogenic roles, including cell proliferation, anchorage-independent cell growth, cell migration and invasion, and human umbilical vein endothelial cell (HUVEC) tube formation in CRC-derived cells. A customized monoclonal mouse anti-human CEMIP2 antibody probing the PANDER-like domain (anti-289307) counteracted CEMIP2-mediated carcinogenesis in vitro. Cell-SELEX pinpointed an aptamer, aptCEMIP2(101), specifically interacted with the full-length CEMIP2, potentially involving its 3D structure. Treatments with aptCEMIP2(101) significantly reduced CEMIP2-mediated tumorigenesis in vitro. Mesoporous silica nanoparticles (MSN) carrying atpCEMIP2(101) and Dox were fabricated. Dox@MSN, MSN-aptCEMIP2(101), and Dox@MSN-aptCEMIP2(101) significantly suppressed tumorigenesis in vitro compared to the Mock, while Dox@MSN-aptCEMIP2(101) showed substantially higher effects compared to Dox@MSN and MSN-aptCEMIP2(101) in CRC-derived cells. Our study identified a novel oncogene and developed an effective aptamer-based targeted therapeutic strategy.

关键词： Aptamer CEMIP2 Cell migration inducing hyaluronidase 2 Colorectal cancer Mesoporous silica nanoparticle

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Deconvoluting clonal and cellular architecture in IDH-mutant acute myeloid leukemia

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Cell Stem Cell 2025年

作者： Sirenko, Maria Lee, Soobeom Sun, Zhengxi Chaligne, Ronan Loghavi, Sanam Asimomitis, Georgios Brierley, Charlotte K. Bernard, Elsa Cai, Sheng F. Myers, Robert M. Nadorp, Bettina Sango, Junya Lallo, Morgan Levine, Max F. Domenico, Dylan Arango Ossa, Juan E. Medina-Martinez, Juan S. Menghrajani, Kamal Lasry, Audrey Mims, Alice S. Desai, Helee Laganson, Andrea Famulare, Chris Patel, Minal Lozanski, Gerard Bolton, Kelly L. Viny, Aaron D. Roshal, Mikhail Levine, Ross L. Papapetrou, Eirini P. Stein, Eytan M. Landau, Dan A. Eisfeld, Ann-Kathrin Aifantis, Iannis Papaemmanuil, Elli Department of Pathology New York University Grossman School of Medicine New York NY United States Laura and Isaac Perlmutter Cancer Center New York University Grossman School of Medicine New York NY United States Louis V. Gerstner Jr. Graduate School of Biomedical Sciences Memorial Sloan Kettering Cancer Center New York NY United States Computational Oncology Service Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY United States Department of Biology New York University New York NY United States Program for Computational and Systems Biology Sloan Kettering Institute Memorial Sloan Kettering Cancer Center New York 10065 NY United States Department of Hematopathology The University of Texas MD Anderson Cancer Center Houston TX United States Biomedical Systems Laboratory Department of Mechanical Engineering National Technical University of Athens Athens Greece Medical Research Council Weatherall Institute of Molecular Medicine University of Oxford Oxford United Kingdom NIHR Biomedical Research Centre University of Oxford Oxford United Kingdom Leukemia Service Department of Medicine Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY United States Human Oncology and Pathogenesis Program Memorial Sloan Kettering Cancer Center New York NY United States Center for Hematologic Malignancies Memorial Sloan Kettering Cancer Center New York NY United States Tri-Institutional MD-PhD Program Weill Cornell Medicine Rockefeller University Memorial Sloan Kettering Cancer Center New York NY United States Division of Precision Medicine Department of Medicine New York University School of Medicine New York NY United States Department of Oncological Sciences Tisch Cancer Institute Center for Advancement of Blood Cancer Therapies Icahn School of Medicine at Mount Sinai New York NY United States Vilcek Institute of Graduate Biomedical Sciences NYU Grossman School of Medicine New Yor

Isocitrate dehydrogenase 1/2 (IDH) mutations are early initiating events in acute myeloid leukemia (AML). The complex clonal architecture and cellular heterogeneity in IDH-mutant AML underlies the heterogeneous clinical presentation and outcomes. Integrating single-cell genotyping and transcriptomics, we demonstrate a stem-like and inflammatory phenotype of IDH-mutant AML and identify clone-specific programs associated with NPM1, NRAS, and SRSF2 co-mutations. Furthermore, these clones had distinct responses to treatment with combination IDH inhibitors and chemotherapy, including elimination, reconstitution of myeloid differentiation, or retention within progenitor populations. At relapse after IDH inhibitor monotherapy, we identify upregulated stemness, inflammation, mitochondrial metabolism, and anti-apoptotic factors, as well as downregulated major histocompatibility complex (MHC) class II antigen presentation. At the pre-leukemic stage, we observe upregulation of IDH2-associated pathways, including inflammation. We deliver a detailed phenotyping of IDH-mutant AML and a framework for dissecting contributions of recurrently mutated genes in AML at diagnosis and following therapy, with implications for precision medicine. © 2025

关键词： acute myeloid leukemia cellular hierarchy clonal architecture clonal evolution IDH inhibitors IDH1/2 mutations relapse single-cell transcriptomics targeted therapy treatment resistance

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