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Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes.
Isobe, Tomoya; Kucinski, Iwo; Barile, Melania; Wang, Xiaonan; Hannah, Rebecca; Bastos, Hugo P; Chabra, Shirom; Vijayabaskar, M S; Sturgess, Katherine H M; Williams, Matthew J; Giotopoulos, George; Marando, Ludovica; Li, Juan; Rak, Justyna; Gozdecka, Malgorzata; Prins, Daniel; Shepherd, Mairi S; Watcham, Sam; Green, Anthony R; Kent, David G; Vassiliou, George S; Huntly, Brian J P; Wilson, Nicola K; Göttgens, Berthold.
Afiliación
  • Isobe T; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Kucinski I; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Barile M; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Wang X; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Hannah R; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Bastos HP; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Chabra S; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Vijayabaskar MS; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Sturgess KHM; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Williams MJ; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Giotopoulos G; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Marando L; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Li J; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Rak J; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK; Hematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
  • Gozdecka M; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK; Hematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
  • Prins D; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Shepherd MS; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Watcham S; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Green AR; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Kent DG; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK; York Biomedical Research Institute, Department of Biology, University of York, York, UK.
  • Vassiliou GS; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK; Hematological Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.
  • Huntly BJP; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK.
  • Wilson NK; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK. Electronic address: nkw22@cam.ac.uk.
  • Göttgens B; Wellcome-MRC Cambridge Stem Cell Institute, Department of Hematology, University of Cambridge, Cambridge, UK. Electronic address: bg200@cam.ac.uk.
Cell Genom ; 3(12): 100426, 2023 Dec 13.
Article en En | MEDLINE | ID: mdl-38116120
ABSTRACT
Acute myeloid leukemia (AML) and myeloid neoplasms develop through acquisition of somatic mutations that confer mutation-specific fitness advantages to hematopoietic stem and progenitor cells. However, our understanding of mutational effects remains limited to the resolution attainable within immunophenotypically and clinically accessible bulk cell populations. To decipher heterogeneous cellular fitness to preleukemic mutational perturbations, we performed single-cell RNA sequencing of eight different mouse models with driver mutations of myeloid malignancies, generating 269,048 single-cell profiles. Our analysis infers mutation-driven perturbations in cell abundance, cellular lineage fate, cellular metabolism, and gene expression at the continuous resolution, pinpointing cell populations with transcriptional alterations associated with differentiation bias. We further develop an 11-gene scoring system (Stem11) on the basis of preleukemic transcriptional signatures that predicts AML patient outcomes. Our results demonstrate that a single-cell-resolution deep characterization of preleukemic biology has the potential to enhance our understanding of AML heterogeneity and inform more effective risk stratification strategies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Genom Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Genom Año: 2023 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos