Stem cell factor as a single agent induces selective proliferation of the Philadelphia chromosome positive fraction of chronic myeloid leukemia CD34(+) cells.
The interaction between p145(c-KIT) and p210(bcr-abl) in transduced cell lines, and the selective outgrowth of normal progenitors during long-term culture of chronic myeloid leukemia (CML) cells on stroma deficient in stem-cell factor (SCF) suggests that the response of CML cells to SCF may be abnormal. We examined the proliferative effect of SCF(100 ng/mL), provided as the sole stimulus, on individual CD34(+) cells from five normal donors and five chronic-phase CML patients. Forty-eight percent of isolated single CML CD34(+) cells proliferated after 6 days of culture to a mean of 18 cells, whereas only 8% of normal CD34(+) cells proliferated (mean number of cells generated was 4). SCF, as a single agent, supported the survival and expansion of colony-forming unit-granulocyte-macrophage (CFU-GM) from CML CD34(+)CD38(+) cells and the more primitive CML CD34(+)CD38(-) cells. These CFU-GM colonies were all bcr-abl positive, showing the specificity of SCF stimulation for the leukemic cell population. Coculture of CML and normal CD34(+) cells showed exclusive growth of Ph+ cells, suggesting that growth in SCF alone is not dependent on secretion of cytokines by CML cells. SCF augmentation of beta1-integrin-mediated adhesion of CML CD34(+) cells to fibronectin was not increased when compared with the effect on normal CD34(+) cells, suggesting that the proliferative and adhesive responses resulting from SCF stimulation are uncoupled. The increased proliferation may contribute to the accumulation of leukemic progenitors, which is a feature of CML.
Moore
S
S
Leukemia Research Laboratory, Division of Haematology, Hanson Centre for Cancer Research, IMVS, Adelaide, SA, Australia. sarah.moore@invs.sa.gov.au
Haylock
D N
DN
Lévesque
J P
JP
McDiarmid
L A
LA
Samels
L M
LM
To
L B
LB
Simmons
P J
PJ
Hughes
T P
TP
D000328:Adult; D018952:Antigens, CD34; D001853:Bone Marrow / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016895:Culture Media, Serum-Free; D005260:Female; D005353:Fibronectins; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000502:physiology; D016298:Hematopoietic Cell Growth Factors / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008297:Male; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010677:Philadelphia Chromosome; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics; D019089:Stem Cell Factor / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D018952:Antigens, CD34; D016895:Culture Media, Serum-Free; D005353:Fibronectins; D016298:Hematopoietic Cell Growth Factors; D009363:Neoplasm Proteins; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D016044:Fusion Proteins, bcr-abl