title: Acute myeloid leukemia does not deplete normal hematopoietic stem cells but induces cytopenias by impeding their differentiation.
abstract: Acute myeloid leukemia (AML) induces bone marrow (BM) failure in patients, predisposing them to life-threatening infections and bleeding. The mechanism by which AML mediates this complication is unknown but one widely accepted explanation is that AML depletes the BM of hematopoietic stem cells (HSCs) through displacement. We sought to investigate how AML affects hematopoiesis by quantifying residual normal hematopoietic subpopulations in the BM of immunodeficient mice transplanted with human AML cells with a range of genetic lesions. The numbers of normal mouse HSCs were preserved whereas normal progenitors and other downstream hematopoietic cells were reduced following transplantation of primary AMLs, findings consistent with a differentiation block at the HSC-progenitor transition, rather than displacement. Once removed from the leukemic environment, residual normal hematopoietic cells differentiated normally and outcompeted steady-state hematopoietic cells, indicating that this effect is reversible. We confirmed the clinical significance of this by ex vivo analysis of normal hematopoietic subpopulations from BM of 16 patients with AML. This analysis demonstrated that the numbers of normal CD34(+)CD38(-) stem-progenitor cells were similar in the BM of AML patients and controls, whereas normal CD34(+)CD38(+) progenitors were reduced. Residual normal CD34(+) cells from patients with AML were enriched in long-term culture, initiating cells and repopulating cells compared with controls. In conclusion the data do not support the idea that BM failure in AML is due to HSC depletion. Rather, AML inhibits production of downstream hematopoietic cells by impeding differentiation at the HSC-progenitor transition.
authors.affiliation: Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
authors.forename: Farideh
authors.initials: F
authors.lastname: Miraki-Moud
authors.forename: Fernando
authors.initials: F
authors.lastname: Anjos-Afonso
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Hodby
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Griessinger
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Rosignoli
authors.forename: Debra
authors.initials: D
authors.lastname: Lillington
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.forename: Jeff K
authors.initials: JK
authors.lastname: Davies
authors.forename: Jamie
authors.initials: J
authors.lastname: Cavenagh
authors.forename: Matthew
authors.initials: M
authors.lastname: Smith
authors.forename: Heather
authors.initials: H
authors.lastname: Oakervee
authors.forename: Samir
authors.initials: S
authors.lastname: Agrawal
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.forename: David C
authors.initials: DC
authors.lastname: Taussig
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D018709:Statistics, Nonparametric
chemical_list: D018952:Antigens, CD34; D051997:ADP-ribosyl Cyclase 1
keywords: anemia; neutropenia; thrombocytopenia; xenotransplant
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