title: Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs.
abstract: Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is currently the leading strategy to manage acute myeloid leukemia (AML). However, treatment-related morbidity limits the patient generalizability of HSCT use, and the survival of leukemic stem cells (LSCs) within protective areas of the bone marrow (BM) continues to lead to high relapse rates. Despite growing appreciation for the significance of the LSC microenvironment, it has remained unresolved whether LSCs preferentially situate within normal HSC niches or whether their niche requirements are more promiscuous. Here, we provide functional evidence that the spatial localization of phenotypically primitive human AML cells is restricted to niche elements shared with their normal counterparts, and that their intrinsic ability to initiate and retain occupancy of these niches can be rivaled by healthy hematopoietic stem and progenitor cells (HSPCs). When challenged in competitive BM repopulation assays, primary human leukemia-initiating cells (L-ICs) can be consistently outperformed by HSPCs for BM niche occupancy in a cell dose-dependent manner that ultimately compromises long-term L-IC renewal and subsequent leukemia-initiating capacity. The effectiveness of this approach could be demonstrated using cytokine-induced mobilization of established leukemia from the BM that facilitated the replacement of BM niches with transplanted HSPCs. These findings identify a functional vulnerability of primitive leukemia cells, and suggest that clinical development of these novel transplantation techniques should focus on the dissociation of L-IC-niche interactions to improve competitive replacement with healthy HSPCs during HSCT toward increased survival of patients.
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Boyd
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Clinton J V
authors.initials: CJ
authors.lastname: Campbell
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Claudia I
authors.initials: CI
authors.lastname: Hopkins
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Aline
authors.initials: A
authors.lastname: Fiebig-Comyn
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Russell
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Jelena
authors.initials: J
authors.lastname: Ulemek
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Ronan
authors.initials: R
authors.lastname: Foley
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.affiliation: Department of Medicine, Division of Hematology, Schulich School of Medicine, University of Western Ontario, London, Ontario N6A 3K7, Canada.
authors.forename: Anargyros
authors.initials: A
authors.lastname: Xenocostas
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Collins
authors.affiliation: Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada Stem Cell and Cancer Research Institute; Department of Biochemistry and Biomedical Sciences; Department of Chemistry and Chemical Biology; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4L8, Canada mbhatia@mcmaster.ca.
authors.forename: Mickie
authors.initials: M
authors.lastname: Bhatia
mesh_terms: D000704:Analysis of Variance; D001853:Bone Marrow / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology / Q000628:therapy*; D008856:Microscopy, Fluorescence; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D055153:Stem Cell Niche / Q000502:physiology*; D014184:Transplantation, Homologous; D059016:Tumor Microenvironment / Q000502:physiology*