Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development.
Hematopoietic stem cells (HSCs) reside in regulatory niches in the bone marrow (BM). Although HSC niches have been extensively characterized, the role of endosteal osteoblasts (OBs) in HSC regulation requires further clarification, and the role of OBs in regulating leukemic stem cells (LSCs) is not well studied. We used an OB visualization and ablation mouse model to study the role of OBs in regulating normal HSCs and chronic myelogenous leukemia (CML) LSCs. OB ablation resulted in increase in cells with a LSK Flt3(-)CD150(+)CD48(-) long-term HSC (LTHSC) phenotype but reduction of a more highly selected LSK Flt3(-)CD34(-)CD49b(-)CD229(-) LTHSC subpopulation. LTHSCs from OB-ablated mice demonstrated loss of quiescence and reduced long-term engraftment and self-renewal capacity. Ablation of OB in a transgenic CML mouse model resulted in accelerated leukemia development with reduced survival compared with control mice. The notch ligand Jagged-1 was overexpressed on CML OBs. Normal and CML LTHSCs cultured with Jagged-1 demonstrated reduced cell cycling, consistent with a possible role for loss of Jagged-1 signals in altered HSC and LSC function after OB ablation. These studies support an important role for OBs in regulating quiescence and self-renewal of LTHSCs and a previously unrecognized role in modulating leukemia development in CML.
Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA; and.
Marisa
M
Bowers
Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA; and.
Bin
B
Zhang
Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA; and.
Yinwei
Y
Ho
Division of Hematology-Oncology, Department of Medicine, University of Alabama Birmingham, Birmingham, AL.
Puneet
P
Agarwal
Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA; and.
Ching-Cheng
CC
Chen
Division of Hematology-Oncology, Department of Medicine, University of Alabama Birmingham, Birmingham, AL.
Ravi
R
Bhatia
D055011:Ablation Techniques; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001853:Bone Marrow / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000473:pathology*; D010006:Osteoblasts / Q000166:cytology*; D000072099:Serrate-Jagged Proteins
D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins