title: Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche.
abstract: Multipotent stromal cells (MSCs) and their osteoblastic lineage cell (OBC) derivatives are part of the bone marrow (BM) niche and contribute to hematopoietic stem cell (HSC) maintenance. Here, we show that myeloproliferative neoplasia (MPN) progressively remodels the endosteal BM niche into a self-reinforcing leukemic niche that impairs normal hematopoiesis, favors leukemic stem cell (LSC) function, and contributes to BM fibrosis. We show that leukemic myeloid cells stimulate MSCs to overproduce functionally altered OBCs, which accumulate in the BM cavity as inflammatory myelofibrotic cells. We identify roles for thrombopoietin, CCL3, and direct cell-cell interactions in driving OBC expansion, and for changes in TGF-β, Notch, and inflammatory signaling in OBC remodeling. MPN-expanded OBCs, in turn, exhibit decreased expression of many HSC retention factors and severely compromised ability to maintain normal HSCs, but effectively support LSCs. Targeting this pathological interplay could represent a novel avenue for treatment of MPN-affected patients and prevention of myelofibrosis.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Koen
authors.initials: K
authors.lastname: Schepers
authors.forename: Eric M
authors.initials: EM
authors.lastname: Pietras
authors.forename: Damien
authors.initials: D
authors.lastname: Reynaud
authors.forename: Johanna
authors.initials: J
authors.lastname: Flach
authors.forename: Mikhail
authors.initials: M
authors.lastname: Binnewies
authors.forename: Trit
authors.initials: T
authors.lastname: Garg
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.forename: Edward C
authors.initials: EC
authors.lastname: Hsiao
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000502:physiology*; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D054405:Chemokine CCL3 / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007938:Leukemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D014411:Neoplastic Stem Cells / Q000502:physiology*; D055728:Primary Myelofibrosis / Q000209:etiology / Q000503:physiopathology*; D051880:Receptors, Notch / Q000378:metabolism; D055153:Stem Cell Niche; D013926:Thrombopoietin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D054405:Chemokine CCL3; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta; D013926:Thrombopoietin