Chronic myelomonocytic leukemia requires granulocyte-macrophage colony-stimulating factor for growth in vitro and in vivo.
OBJECTIVE
Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease with no effective treatments or cure. Several factors have been implicated in its pathogenesis. In the current study, we studied the dependence of CMML on granulocyte-macrophage colony-stimulating factor (GM-CSF).


METHODS
We used in vitro colony assays in methylcellulose where CMML cells were tested in the presence or absence of the specific GM-CSF antagonist E21R. We also developed an in vivo model in which CMML cells were tested for their ability to engraft into immunodeficient mice transgenic for human GM-CSF.


RESULTS
Bone marrow cells from seven of seven patients with CMML formed spontaneous colonies that were sensitive to E21R treatment, with reduction in colony growth by up to 92%. E21R also inhibited colony formation by CMML patient cells stimulated by exogenously added GM-CSF but not interleukin-3. In in vivo experiments we observed engraftment of CMML cells (but not normal cells) in immunodeficient mice transgenic for human GM-CSF. None engrafted in nontransgenic mice. Cell dose escalation showed that the optimal number was 0.5 to 1 x 10(8) peripheral blood mononuclear cells per mouse, which is equivalent to an infusion of 0.2 to 3.6 x 10(6) CD34(+) cells. Time course experiments showed that maximal engraftment occurred 6 weeks after injection.


CONCLUSIONS
These results demonstrate that in some CMML patients, GM-CSF produced by either autocrine or paracrine mechanisms is a major growth determinant. The results suggest that therapies directed at blocking this cytokine could control the growth of some CMML patients in vivo.
Ramshaw
Hayley S
HS
Cytokine Receptor Laboratory, Division of Human Immunology, IMVS, Adelaide, South Australia, Australia.
Bardy
Peter G
PG
Lee
Melissa A
MA
Lopez
Angel F
AF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001752:Blast Crisis / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D016178:Granulocyte-Macrophage Colony-Stimulating Factor