title: Evolution of acute myelogenous leukemia stem cell properties after treatment and progression.
abstract: Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor γ chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered.
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, NY;
authors.forename: Tzu-Chieh
authors.identifier: 0000-0002-2913-9319
authors.initials: TC
authors.lastname: Ho
authors.affiliation: Department of Medicine, J. P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: Mark
authors.initials: M
authors.lastname: LaMere
authors.affiliation: Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO;
authors.forename: Brett M
authors.initials: BM
authors.lastname: Stevens
authors.affiliation: Genomics Research Center, J. P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: John M
authors.identifier: 0000-0001-9875-5994
authors.initials: JM
authors.lastname: Ashton
authors.affiliation: Genomics Research Center, J. P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: Jason R
authors.identifier: 0000-0002-0341-0860
authors.initials: JR
authors.lastname: Myers
authors.affiliation: Department of Medicine, J. P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: Kristen M
authors.initials: KM
authors.lastname: O'Dwyer
authors.affiliation: Department of Medicine, J. P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: Jane L
authors.identifier: 0000-0002-3386-8469
authors.initials: JL
authors.lastname: Liesveld
authors.affiliation: Department of Medicine, J. P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: Jason H
authors.initials: JH
authors.lastname: Mendler
authors.affiliation: Department of Pharmacology in Medicine, Weill Medical College of Cornell University, New York, NY;
authors.forename: Monica
authors.initials: M
authors.lastname: Guzman
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Morrissette
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Eunice S
authors.initials: ES
authors.lastname: Wang
authors.affiliation: Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.affiliation: Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO;
authors.forename: Craig T
authors.identifier: 0000-0003-0869-3465
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Department of Medicine, J. P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;
authors.forename: Michael W
authors.identifier: 0000-0001-9890-8815
authors.initials: MW
authors.lastname: Becker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000276:immunology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000473:pathology*; D011446:Prospective Studies; D012008:Recurrence; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor