Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice.
The myelomagenic capacity of clonotypic myeloma cells in G-CSF mobilized blood was tested by xenotransplant. Intracardiac (IC) injection of NOD SCID mice with peripheral cells from 5 patients who had aggressive myeloma led to lytic bone lesions, human Ig in the serum, human plasma cells, and a high frequency of clonotypic cells in the murine bone marrow (BM). Human B and plasma cells were detected in BM, spleen, and blood. Injection of ex vivo multiple myeloma cells directly into the murine sternal BM (intraosseus injection [IO]) leads to lytic bone lesions, BM plasma cells, and a high frequency of clonotypic cells in the femoral BM. This shows that myeloma has spread from the primary injection site to distant BM locations. By using a cellular limiting dilution PCR assay to quantify clonotypic B lineage cells, we confirmed that peripheral myeloma cells homed to the murine BM after IC and IO injection. The myeloma progenitor undergoes self-renewal in murine BM, as demonstrated by the transfer of human myeloma to a secondary recipient mouse. For 6 of 7 patients, G-CSF mobilized cells from patients who have minimal disease, taken at the time of mobilization or after cryopreservation, included myeloma progenitors as identified by engraftment of clonotypic cells and/or lytic bone disease in mice. This indicates that myeloma progenitors are mobilized into the blood by cyclophosphamide/G-CSF. Their ability to generate myeloma in a xenotransplant model implies that such progenitors are also myelomagenic when reinfused into patients, and suggests the need for an effective strategy to purge them before transplant.
Pilarski
L M
LM
Departments of Oncology and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Hipperson
G
G
Seeberger
K
K
Pruski
E
E
Coupland
R W
RW
Belch
A R
AR
D000818:Animals; D000951:Antigens, Neoplasm / Q000032:analysis; D014408:Biomarkers, Tumor; D001853:Bone Marrow / Q000473:pathology; D016465:Bone Marrow Purging; D001859:Bone Neoplasms / Q000473:pathology; D019070:Cell Lineage; D015925:Cryopreservation; D003520:Cyclophosphamide / Q000494:pharmacology; D005269:Femur / Q000473:pathology; D006085:Graft Survival; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006352:Heart Ventricles; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007267:Injections; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000097:blood* / Q000145:classification / Q000150:complications / Q000473:pathology; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual; D009360:Neoplastic Cells, Circulating; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000637:transplantation*; D010014:Osteolysis / Q000209:etiology; D013045:Species Specificity; D013249:Sternum; D014021:Tissue Preservation; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000235:genetics
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D001613:beta 2-Microglobulin; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide