Journal article
A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia
Nature cancer
25 Nov 2024
PMID: 39587259
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia
- Creators
- Jason Xu - University of PennsylvaniaChangya Chen - Children's Hospital of PhiladelphiaJonathan H Sussman - University of PennsylvaniaSatoshi Yoshimura - St. Jude Children's Research HospitalTiffaney Vincent - Children's Hospital of PhiladelphiaPetri Pölönen - St. Jude Children's Research HospitalJianzhong Hu - St. Jude Children's Research HospitalShovik Bandyopadhyay - University of PennsylvaniaOmar Elghawy - Children's Hospital of PhiladelphiaWenbao Yu - Children's Hospital of PhiladelphiaJoseph Tumulty - Children's Hospital of PhiladelphiaChia-Hui Chen - Children's Hospital of PhiladelphiaElizabeth Y Li - Children's Hospital of PhiladelphiaCaroline Diorio - Children's Hospital of PhiladelphiaRawan Shraim - Children's Hospital of PhiladelphiaHaley Newman - Children's Hospital of PhiladelphiaLahari Uppuluri - Children's Hospital of PhiladelphiaAlexander Li - Children's Hospital of PhiladelphiaGregory M Chen - University of PennsylvaniaDavid W Wu - University of PennsylvaniaYang-Yang Ding - Children's Hospital of PhiladelphiaJessica A Xu - Children's Hospital of PhiladelphiaDamjan Karanfilovski - Children's Hospital of PhiladelphiaTristan Lim - University of PennsylvaniaMiles Hsu - University of PennsylvaniaAnusha Thadi - Children's Hospital of PhiladelphiaKyung Jin Ahn - Children's Hospital of PhiladelphiaChi-Yun Wu - University of PennsylvaniaJacqueline Peng - University of PennsylvaniaYusha Sun - Yale UniversityAlice Wang - University of PennsylvaniaRushabh Mehta - Yale UniversityDavid Frank - Children's Hospital of PhiladelphiaLauren Meyer - Seattle Children's HospitalMignon L Loh - Seattle Children's HospitalElizabeth A Raetz - NYU Langone HealthZhiguo Chen - University of FloridaBrent L Wood - Children's Hospital of Los AngelesMeenakshi Devidas - St. Jude Children's Research HospitalKimberly P Dunsmore - University of Virginia Children's HospitalStuart S Winter - University of Minnesota Children's HospitalTi-Cheng Chang - St. Jude Children's Research HospitalGang Wu - St. Jude Children's Research HospitalStanley B Pounds - St. Jude Children's Research HospitalNancy R Zhang - University of PennsylvaniaWilliam Carroll - NYU Langone HealthStephen P Hunger - University of PennsylvaniaKathrin Bernt - Children's Hospital of PhiladelphiaJun J Yang - St. Jude Children's Research HospitalCharles G Mullighan - St. Jude Children's Research HospitalKai Tan - University of PennsylvaniaDavid T Teachey - University of Pennsylvania
- Publication Details
- Nature cancer
- Publisher
- NATURE PORTFOLIO; BERLIN
- Number of pages
- 43
- Grant note
- U10 CA18099 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) U10 CA180886 / NCI NIH HHS R03 CA 256550 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) F30 CA268782 / NCI NIH HHS St. Baldrick's Foundation / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01 CA264837 / NCI NIH HHS U2C CA233285 / NCI NIH HHS U24 CA196173 / NCI NIH HHS U54 HL165442 / NHLBI NIH HHS U24 CA114766 / NCI NIH HHS
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:001362645100001
- Scopus ID
- 2-s2.0-85210167067
- Other Identifier
- 991021969154804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology