2. Academic Validation
  3. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts

Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts

  • Blood. 2014 Oct 30;124(18):2834-46. doi: 10.1182/blood-2013-07-517219.
Maria Krevvata 1,  Barbara C Silva 1,  John S Manavalan 1,  Marta Galan-Diez 1,  Aruna Kode 1,  Brya Grace Matthews 2,  David Park 3,  Chiyuan A Zhang 1,  Naomi Galili 4,  Thomas L Nickolas 5,  David W Dempster 6,  William Dougall 7,  Julie Teruya-Feldstein 3,  Aris N Economides 8,  Ivo Kalajzic 2,  Azra Raza 4,  Ellin Berman 9,  Siddhartha Mukherjee 10,  Govind Bhagat 11,  Stavroula Kousteni 1
Affiliations

Affiliations

  • 1 Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY;
  • 2 Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT;
  • 3 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY;
  • 4 Myelodysplastic Syndromes Center and.
  • 5 Department of Medicine, Division of Nephrology, College of Physicians and Surgeons, Columbia University, New York, NY;
  • 6 Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY;
  • 7 Amgen Inc., Seattle, WA;
  • 8 Bone and Cartilage Biology Group, Genome Engineering Technologies Group, Regeneron Pharmaceuticals Inc., Tarrytown, NY;
  • 9 Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY;
  • 10 Department of Medicine, Division of Hematology and Oncology, and.
  • 11 Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY.
PMID: 25139351 DOI: 10.1182/blood-2013-07-517219
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.

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