ArticleNature cancer2025
A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia.
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Article in Nature cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21citing papers in PubMed
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Who cites it
21 citing papers in PubMed.
- The machine-learning classifier ALLCatchR2 identifies 20 T-ALL subtypes across cohorts and age groups.HemaSphere · 2026Article
- A genomic and epigenomic lens into the biology of acute lymphoblastic leukaemia.Nature reviews. Cancer · 2026Review
- Plasticity under pressure: biology and detection of lineage switch in acute leukemia.Leukemia · 2026Review
- Co-option of lineage plasticity as a hallmark of multipotent acute leukemias.Blood neoplasia · 2026Review
- Evaluation of Darifenacin for T-Cell Acute Lymphoblastic Leukemia: Selective Targeting of the Non-Neuronal Cholinergic System and Lysosomal Cathepsins.International journal of molecular sciences · 2026Article
- Article
- Single-Cell Transcriptomic Profiling Reveals Dual Antitumor and Adaptive Resistance Mechanisms of a Novel HSP90 Inhibitor, SP11, in T-Cell Acute Lymphoblastic Leukemic Cells and DLA Mouse Model.International journal of molecular sciences · 2026Article
- CCR4 expression defines a targetable subset of T-cell acute lymphoblastic leukemia.Blood advances · 2026Article
- Proteomics landscape of early T-cell precursor acute lymphoblastic leukemia reveals deficient oxidative phosphorylation signatures.Cell reports. Medicine · 2026Article
- CD7-Specific Polymersomal Vincristine Delivery Potentiates Chemotherapy in T‑Cell Acute Lymphoblastic Leukemia.Polymer science & technology (Washington, D.C.) · 2026Article
- Emerging genomic biomarkers in diagnosis and classification of T-cell acute lymphoblastic leukemia.Hematology. American Society of Hematology. Education Program · 2025Review
- A non-canonical lymphoblast in refractory childhood T-cell leukaemia.Nature communications · 2025Article
- Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98-rearranged leukemia.Blood · 2025Article
- Hematopoietic Stem Cell Hierarchies as Novel Biomarkers of Drug Response in Myelodysplastic Syndromes and Acute Myeloid Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Review
- Pediatric acute leukemias and myelodysplastic syndromes, progress and challenges: introduction to a review series.Haematologica · 2025Article
- Sketching T cell atlases in the single-cell era: challenges and recommendations.Immunology and cell biology · 2025Review
- STAT1-mediated interferon signatures are associated with preclinical JAK inhibitor sensitivity in T-ALL.Blood · 2025Article
- Single-cell panleukemia signatures of HSPC-like blasts predict drug response and clinical outcome.Blood · 2025Article
- Native stem cell transcriptional circuits define cardinal features of high-risk leukemia.The Journal of experimental medicine · 2025Article
- Review
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Authors and funding
52 authors.
Jason Xu *Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Changya Chen *Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jonathan H SussmanGraduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-3057-3550
Satoshi YoshimuraDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Tiffaney VincentDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Petri PölönenDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0001-6128-9985
Jianzhong HuDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Shovik BandyopadhyayMedical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Omar ElghawyDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Wenbao YuDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Joseph TumultyDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID 0000-0001-7531-2066
Chia-Hui ChenDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID 0000-0001-5239-1574
Elizabeth Y LiDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Caroline DiorioDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Rawan ShraimDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Haley NewmanDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Lahari UppuluriDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID 0000-0002-7217-892X
Alexander LiDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Gregory M ChenGraduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
David W WuGraduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0001-6197-7091
Yang-Yang DingDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID 0000-0003-1588-2571
Jessica A XuDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Damjan KaranfilovskiDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Tristan LimMedical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Miles HsuMedical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Anusha ThadiDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID 0000-0002-1271-0398
Kyung Jin AhnDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Chi-Yun WuGraduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jacqueline PengGraduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Yusha SunMedical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0003-4835-3000
Alice WangGraduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-1789-8561
Rushabh MehtaYale School of Medicine, New Haven, CT, USA.
David FrankDivision of Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Lauren MeyerThe Ben Town Center for Childhood Cancer Research, Seattle Children's Hospital, Seattle, WA, USA.
Mignon L LohThe Ben Town Center for Childhood Cancer Research, Seattle Children's Hospital, Seattle, WA, USA.ORCID 0000-0003-4099-4700
Elizabeth A RaetzDepartment of Pediatrics and Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
Zhiguo ChenDepartment of Biostatistics, University of Florida, Gainesville, FL, USA.
Brent L WoodDepartment of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Meenakshi DevidasDepartment of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0002-1099-3478
Kimberly P DunsmoreDivision of Oncology, University of Virginia Children's Hospital, Charlottesville, VA, USA.
Stuart S WinterChildren's Minnesota Hospital, Minneapolis, MN, USA.ORCID 0000-0003-3583-7727
Ti-Cheng ChangCenter for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0001-5302-9147
Gang WuCenter for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0002-1678-5864
Stanley B PoundsDepartment of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0002-9167-2114
Nancy R ZhangDepartment of Statistics, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-0880-5749
William CarrollDepartment of Pediatrics and Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
Stephen P HungerDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kathrin BerntDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID 0000-0002-0691-356X
Jun J YangDepartment of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0002-0770-9659
Charles G MullighanDepartment of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0002-1871-1850
Kai TanDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. tank1@chop.edu.ORCID 0000-0002-9104-5567
David T TeacheyDivision of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA. teacheyd@chop.edu.ORCID 0000-0001-7373-8987
Funding
NCTN BIQSFP ANBL1531 (NRT)U10CA180886 · NCI · PUBLIC HEALTH INSTITUTE · PI Douglas S. Hawkins · 2014 to 2026
$390.6MCOG SDMC - Statistics CoreU10CA180899 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI TODD A ALONZO · 2014 to 2026
$132.8MCOG U24 Funding 2026-2027U24CA196173 · NCI · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · PI Mignon Lee-Cheun Loh, Nilsa Del Carmen Ramirez Milan · 2015 to 2026
$62.5MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007170 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI BRASS, LAWRENCE F · 1985 to 2022
$54.0MSupport for Human Specimen Banking in NCI-Supported Cancer Clinical TrialsU24CA114766 · NCI · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · PI RAMIREZ MILAN, NILSA DEL CARMEN · 2005 to 2014
$14.5MData Analysis UnitU2CCA233285 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI HUNGER, STEPHEN PATRICK, TAN, KAI · 2018 to 2023
$13.2MOrgan Specific Project - HeartU54HL165442 · NHLBI · CHILDREN'S HOSP OF PHILADELPHIA · PI MOFFITT, JEFFREY, PEI, LIMING · 2022 to 2025
$7.6MImproving risk allocation and developing novel therapies for children with T-ALL and T-LLR01CA193776 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI Terzah M Horton, ADAM B OLSHEN · 2015 to 2026
$6.2MBiomarkers of dasatinib response and resistance in T-cell acute lymphoblastic leukemiaR01CA264837 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI TEACHEY, DAVID T., YANG, JUN J. · 2021 to 2025
$3.0MElucidating Critical Dependencies Underlying Therapeutic Evasion in Philadelphia Chromosome-like Acute Lymphoblastic LeukemiaK08CA273531 · NCI · JOHNS HOPKINS UNIVERSITY · PI Yang-Yang Ding · 2022 to 2026
$738kGenomic Profiling of T-cell Acute Lymphoblastic Leukemia in ChildrenR03CA256550 · NCI · CHILDREN'S HOSP OF PHILADELPHIA · PI MULLIGHAN, CHARLES G., TEACHEY, DAVID T. · 2021 to 2021
$382kAnalysis of Developmental Arrest and Treatment Resistance in High-risk T-ALLF30CA268782 · NCI · UNIVERSITY OF PENNSYLVANIA · PI XU, JASON · 2022 to 2024
$141kNCI NIH HHS F30 CA268782NCI NIH HHS F30 CA277965NCI NIH HHS R01 CA193776NCI NIH HHS R01 CA264837NCI NIH HHS R03 CA256550NCI NIH HHS U10 CA180886NCI NIH HHS U10 CA180899NCI NIH HHS U24 CA114766NCI NIH HHS U24 CA196173NCI NIH HHS U2C CA233285NHLBI NIH HHS U54 HL165442NIGMS NIH HHS T32 GM007170U.S. Department of Health & Human Services | National Institutes of Health (NIH) R03 CA 256550U.S. Department of Health & Human Services | National Institutes of Health (NIH) St. Baldrick's FoundationU.S. Department of Health & Human Services | National Institutes of Health (NIH) T32 GM07170U.S. Department of Health & Human Services | National Institutes of Health (NIH) U10 CA18099U.S. Department of Health & Human Services | National Institutes of Health (NIH) X01 HD100702
Abstract
Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL.
Indexed as
Bone Marrow CellsDrug Resistance, NeoplasmPrecursor T-Cell Lymphoblastic Leukemia-LymphomaAdolescentChildChild, PreschoolFemaleHumansInfantMaleMutationReceptor, Notch1Single-Cell AnalysisNOTCH1 protein, humanReceptor, Notch1
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