Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells.
The host tissue microenvironment influences malignant cell proliferation and metastasis, but little is known about how tumor-induced changes in the microenvironment affect benign cellular ecosystems. Applying dynamic in vivo imaging to a mouse model, we show that leukemic cell growth disrupts normal hematopoietic progenitor cell (HPC) bone marrow niches and creates abnormal microenvironments that sequester transplanted human CD34+ (HPC-enriched) cells. CD34+ cells in leukemic mice declined in number over time and failed to mobilize into the peripheral circulation in response to cytokine stimulation. Neutralization of stem cell factor (SCF) secreted by leukemic cells inhibited CD34+ cell migration into malignant niches, normalized CD34+ cell numbers, and restored CD34+ cell mobilization in leukemic mice. These data suggest that the tumor microenvironment causes HPC dysfunction by usurping normal HPC niches and that therapeutic inhibition of HPC interaction with tumor niches may help maintain normal progenitor cell function in the setting of malignancy.
Colmone
Angela
A
Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 South Maryland Avenue MC 2115, Chicago, IL 60637, USA.
Amorim
Maria
M
Pontier
Andrea L
AL
Wang
Sheng
S
Jablonski
Elizabeth
E
Sipkins
Dorothy A
DA
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001596:Benzylamines; D001853:Bone Marrow / Q000473:pathology*; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche / Q000473:pathology* / Q000503:physiopathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D001596:Benzylamines; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor