Inhibition of granulocyte-macrophage colony-stimulating factor prevents dissemination and induces remission of juvenile myelomonocytic leukemia in engrafted immunodeficient mice.
Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor alpha (TNFalpha) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFalpha monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.
Iversen
P O
PO
Divisions of Human Immunology and Haematology of the Hanson Centre for Cancer Research, IMVS, Adelaide, S.A., Australia.
Lewis
I D
ID
Turczynowicz
S
S
Hasle
H
H
Niemeyer
C
C
Schmiegelow
K
K
Bastiras
S
S
Biondi
A
A
Hughes
T P
TP
Lopez
A F
AF
D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002648:Child; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000628:therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009368:Neoplasm Transplantation
D000911:Antibodies, Monoclonal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor