Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts Journal Article
| Authors: | Krevvata, M.; Silva, B. C.; Manavalan, J. S.; Galan-Diez, M.; Kode, A.; Matthews, B. G.; Park, D.; Zhang, C. A.; Galili, N.; Nickolas, T. L.; Dempster, D. W.; Dougall, W.; Teruya-Feldstein, J.; Economides, A. N.; Kalajzic, I.; Raza, A.; Berman, E.; Mukherjee, S.; Bhagat, G.; Kousteni, S. |
| Article 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. |
| Keywords: | controlled study; human tissue; osteolysis; acute granulocytic leukemia; disease course; nonhuman; mouse; animal tissue; cell survival; enzyme inhibition; erythropoiesis; tumor volume; animal experiment; animal model; cell differentiation; acute lymphoblastic leukemia; cell lineage; engraftment; myelodysplastic syndrome; cd11b antigen; leukemia cell; cell count; hematopoiesis; osteoclast; lymphopoiesis; stem cell niche; cd45 antigen; osteoblast; osteoprotegerin; osteoclast differentiation factor; serotonin; myelopoiesis; osteocalcin; human; male; female; article; tryptophan hydroxylase |
| Journal Title: | Blood |
| Volume: | 124 |
| Issue: | 18 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2014-10-30 |
| Start Page: | 2834 |
| End Page: | 2846 |
| Language: | English |
| DOI: | 10.1182/blood-2013-07-517219 |
| PROVIDER: | scopus |
| PUBMED: | 25139351 |
| PMCID: | PMC4314530 |
| DOI/URL: | |
| Notes: | Export Date: 1 December 2014 -- Source: Scopus |
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