title: Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis.
abstract: Acute myeloid leukemia (AML) manifests as phenotypically and functionally diverse cells, often within the same patient. Intratumor phenotypic and functional heterogeneity have been linked primarily by physical sorting experiments, which assume that functionally distinct subpopulations can be prospectively isolated by surface phenotypes. This assumption has proven problematic, and we therefore developed a data-driven approach. Using mass cytometry, we profiled surface and intracellular signaling proteins simultaneously in millions of healthy and leukemic cells. We developed PhenoGraph, which algorithmically defines phenotypes in high-dimensional single-cell data. PhenoGraph revealed that the surface phenotypes of leukemic blasts do not necessarily reflect their intracellular state. Using hematopoietic progenitors, we defined a signaling-based measure of cellular phenotype, which led to isolation of a gene expression signature that was predictive of survival in independent cohorts. This study presents new methods for large-scale analysis of single-cell heterogeneity and demonstrates their utility, yielding insights into AML pathophysiology.
authors.affiliation: Departments of Biological Sciences and Systems Biology, Columbia University, New York, NY 10027, USA.
authors.forename: Jacob H
authors.initials: JH
authors.lastname: Levine
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Erin F
authors.initials: EF
authors.lastname: Simonds
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Bendall
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Davis
authors.affiliation: Departments of Biological Sciences and Systems Biology, Columbia University, New York, NY 10027, USA.
authors.forename: El-ad D
authors.initials: el-AD
authors.lastname: Amir
authors.affiliation: Departments of Biological Sciences and Systems Biology, Columbia University, New York, NY 10027, USA.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Tadmor
authors.affiliation: Departments of Biological Sciences and Systems Biology, Columbia University, New York, NY 10027, USA.
authors.forename: Oren
authors.initials: O
authors.lastname: Litvin
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Harris G
authors.initials: HG
authors.lastname: Fienberg
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Astraea
authors.initials: A
authors.lastname: Jager
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Eli R
authors.initials: ER
authors.lastname: Zunder
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Finck
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Gedman
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Ina
authors.initials: I
authors.lastname: Radtke
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: Departments of Biological Sciences and Systems Biology, Columbia University, New York, NY 10027, USA. Electronic address: dpeer@biology.columbia.edu.
authors.forename: Dana
authors.initials: D
authors.lastname: Pe'er
authors.affiliation: Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address: gnolan@stanford.edu.
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
mesh_terms: D001853:Bone Marrow / Q000473:pathology; D002648:Child; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods*; D018740:Genetic Heterogeneity; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D014411:Neoplastic Stem Cells / Q000473:pathology; D059010:Single-Cell Analysis / Q000379:methods*; D059467:Transcriptome