title: Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts.
abstract: The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY;
authors.forename: Maria
authors.initials: M
authors.lastname: Krevvata
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY;
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Silva
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY;
authors.forename: John S
authors.initials: JS
authors.lastname: Manavalan
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY;
authors.forename: Marta
authors.initials: M
authors.lastname: Galan-Diez
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY;
authors.forename: Aruna
authors.initials: A
authors.lastname: Kode
authors.affiliation: Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT;
authors.forename: Brya Grace
authors.initials: BG
authors.lastname: Matthews
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: David
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY;
authors.forename: Chiyuan A
authors.initials: CA
authors.lastname: Zhang
authors.affiliation: Myelodysplastic Syndromes Center and.
authors.forename: Naomi
authors.initials: N
authors.lastname: Galili
authors.affiliation: Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, NY;
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Nickolas
authors.affiliation: Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY;
authors.forename: David W
authors.initials: DW
authors.lastname: Dempster
authors.affiliation: Amgen Inc., Seattle, WA;
authors.forename: William
authors.initials: W
authors.lastname: Dougall
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY;
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Bone and Cartilage Biology Group, Genome Engineering Technologies Group, Regeneron Pharmaceuticals Inc., Tarrytown, NY;
authors.forename: Aris N
authors.initials: AN
authors.lastname: Economides
authors.affiliation: Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT;
authors.forename: Ivo
authors.initials: I
authors.lastname: Kalajzic
authors.affiliation: Myelodysplastic Syndromes Center and.
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY;
authors.forename: Ellin
authors.initials: E
authors.lastname: Berman
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, and.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY;
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kousteni
mesh_terms: D000818:Animals; D002452:Cell Count; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C548240:LP533401; D011743:Pyrimidines