title: A clinically relevant population of leukemic CD34(+)CD38(-) cells in acute myeloid leukemia.
abstract: Relapse of acute myeloid leukemia (AML) is thought to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs), the rare, resistant cells presumed responsible for maintenance of the leukemia and typically enriched in the CD34(+)CD38(-) cell population. Despite the considerable research on LSCs over the past 2 decades, the clinical significance of these cells remains uncertain. However, if clinically relevant, it is expected that LSCs would be enriched in minimal residual disease and predictive of relapse. CD34(+) subpopulations from AML patients were analyzed by flow cytometry throughout treatment. Sorted cell populations were analyzed by fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities (when present) and by transplantation into immunodeficient mice to determine self-renewal capacity. Intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity reliably distinguished leukemic CD34(+)CD38(-) cells capable of engrafting immunodeficient mice from residual normal hematopoietic stem cells that exhibited relatively higher ALDH activity. Minimal residual disease detected during complete remission was enriched for the CD34(+)CD38(-)ALDH(int) leukemic cells, and the presence of these cells after therapy highly correlated with subsequent clinical relapse. ALDH activity appears to distinguish normal from leukemic CD34(+)CD38(-) cells and identifies those AML cells associated with relapse.
authors.affiliation: Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jgerber2@jhmi.edu
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Gerber
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Brownhilda
authors.initials: B
authors.lastname: Ngwang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Milada S
authors.initials: MS
authors.lastname: Vala
authors.forename: Laura
authors.initials: L
authors.lastname: Morsberger
authors.forename: Steven
authors.initials: S
authors.lastname: Galkin
authors.forename: Michael I
authors.initials: MI
authors.lastname: Collector
authors.forename: Brandy
authors.initials: B
authors.lastname: Perkins
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.forename: Constance A
authors.initials: CA
authors.lastname: Griffin
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Sharkis
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D012008:Recurrence; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D051997:ADP-ribosyl Cyclase 1