Autocrine and paracrine growth control by granulocyte-monocyte colony-stimulating factor of acute lymphoblastic leukemia cells.
Blast colony assays were performed on freshly obtained bone marrow samples from 19 newly diagnosed or relapsed children with acute lymphoblastic leukemia (ALL) of B lineage to determine the effect of added granulocyte-monocyte colony-stimulating factor (GM-CSF). Of the 19 marrow samples tested, 7 responded to GM-CSF with a mean increase in ALL blast colonies of 346%. Blast cells from one of the responders chosen for flow cytometric study showed expression of GM-CSF receptors on 38% of cells. These findings prompted us to establish five ALL cell lines of diverse phenotypes to examine the expression of GM-CSF and GM-CSF receptor genes in human leukemia, and to determine the role of GM-CSF in autocrine and paracrine growth control of ALL cells. One line, termed G2, manifested a GM-CSF-mediated autocrine pattern of cell growth with the following features: G2 blast colony growth in a serum-free system without added growth factor was density dependent; exogenous GM-CSF augmented G2 colony formation when the cells were seeded at low density; G2 cells constitutively expressed mRNA for GM-CSF and GM-CSF receptor; G2 cells also produced and secreted measurable amounts of GM-CSF into cell culture supernatant; and, monoclonal anti-GM-CSF antibodies abolished G2 colony growth when added to cultures with cells seeded at low density without growth factors. Of the other four ALL cell lines, three expressed mRNA for GM-CSF receptor and responded in vitro to added GM-CSF with increased blast colony growth; however, none of these four cell lines expressed mRNA for constitutive production of GM-CSF. A fifth ALL cell line lacked receptors for GM-CSF and did not respond in clonogenic assays to added GM-CSF. Thus, a bioregulator of normal hematopoiesis plays a central role in autocrine growth control of G2 ALL cells, and an important paracrine growth-promoting role in three of four other ALL cell lines.
Division of Hematology-Oncology, Hospital for Sick Children, Toronto, Canada.
M H
MH
Freedman
T
T
Grunberger
P
P
Correa
A A
AA
Axelrad
I D
ID
Dube
A
A
Cohen
D002455:Cell Division / Q000187:drug effects; D002648:Child; D016207:Cytokines / Q000494:pharmacology; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016207:Cytokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor