title: Mass Cytometric Functional Profiling of Acute Myeloid Leukemia Defines Cell-Cycle and Immunophenotypic Properties That Correlate with Known Responses to Therapy.
abstract: Acute myeloid leukemia (AML) is characterized by a high relapse rate that has been attributed to the quiescence of leukemia stem cells (LSC), which renders them resistant to chemotherapy. However, this hypothesis is largely supported by indirect evidence and fails to explain the large differences in relapse rates across AML subtypes. To address this, bone marrow aspirates from 41 AML patients and five healthy donors were analyzed by high-dimensional mass cytometry. All patients displayed immunophenotypic and intracellular signaling abnormalities within CD34(+)CD38(lo) populations, and several karyotype- and genotype-specific surface marker patterns were identified. The immunophenotypic stem and early progenitor cell populations from patients with clinically favorable core-binding factor AML demonstrated a 5-fold higher fraction of cells in S-phase compared with other AML samples. Conversely, LSCs in less clinically favorable FLT3-ITD AML exhibited dramatic reductions in S-phase fraction. Mass cytometry also allowed direct observation of the in vivo effects of cytotoxic chemotherapy.
  
  
  CONCLUSIONS
  The mechanisms underlying differences in relapse rates across AML subtypes are poorly understood. This study suggests that known chemotherapy sensitivities of common AML subsets are mediated by cell-cycle differences among LSCs and provides a basis for using in vivo functional characterization of AML cells to inform therapy selection.
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California. Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California. Stanford Cancer Institute, Stanford, California.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Behbehani
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Samusik
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California.
authors.forename: Zach B
authors.initials: ZB
authors.lastname: Bjornson
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California.
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Fantl
authors.affiliation: Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, California. Stanford Cancer Institute, Stanford, California.
authors.forename: Bruno C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California. gnolan@stanford.edu.
authors.forename: Garry P
authors.initials: GP
authors.lastname: Nolan
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000378:metabolism; D001856:Bone Marrow Examination; D002453:Cell Cycle / Q000235:genetics; D016000:Cluster Analysis; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D016130:Immunophenotyping; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D015203:Reproducibility of Results; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers