Suppression of juvenile chronic myelogenous leukemia colony growth by interleukin-1 receptor antagonist.
Bone marrow (BM) and peripheral blood (PB) cells from patients with juvenile chronic myelogenous leukemia (JCML) exhibit spontaneous in vitro proliferation. Several cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 beta (IL-1 beta), and tumor necrosis factor alpha (TNF alpha) have been implicated in supporting the growth of leukemic monocyte-macrophage colonies either by autocrine or paracrine pathways. In seven untreated JCML patients, we investigated the role of IL-1 in the spontaneous growth of these cells by specifically blocking IL-1 receptors. The IL-1 receptor antagonist (IL-1 Ra) was added to the clonogenic assays, and in each case significant (mean = 63%, range = 35% to 82%) inhibition of spontaneous proliferation was observed. Uncultured circulating cells from PB or BM of four out of five patients expressed IL-1 beta-specific mRNA and secreted the protein into the culture supernatants. Moreover, by means of reverse transcriptase-polymerase chain reaction (RT-PCR), we demonstrated that most of the spontaneously growing leukemic colony-forming unit cells (CFU-C) obtained from BM cells of two patients were positive for the presence of the IL-1 beta-specific mRNA. Despite the presence of a measurable amount of GM-CSF in JCML cell culture supernatants, GM-CSF-specific mRNA in CFU-C cells of four cases was not detected by RT-PCR. These data further support a central role for IL-1 beta in the pathogenesis of JCML and suggest that the use of IL-1 Ra could represent a novel therapeutic strategy against this disorder.
Schirò
R
R
Clinica Pediatrica Università di Milano-H.S. Gerardo, Monza, Italy.
Longoni
D
D
Rossi
V
V
Maglia
O
O
Doni
A
A
Arsura
M
M
Carrara
G
G
Masera
G
G
Vannier
E
E
Dinarello
C A
CA
D000328:Adult; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000627:therapeutic use*
D016207:Cytokines; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012333:RNA, Messenger; D012795:Sialoglycoproteins