Interleukin-11 (IL-11) enhances clonal proliferation of acute myelogenous leukemia cells with strong expression of the IL-11 receptor alpha chain and signal transducing gp130.
We examined the effect of recombinant human interleukin (IL)-11 alone or in combination with various colony-stimulating factors (CSFs), including IL-3, granulocyte/macrophage (GM)-CSF, granulocyte (G)-CSF, stem cell factor (SCF), flt3 ligand (FL), and thrombopoietin (TPO), on colony formation by leukemic progenitor cells (L-CFU) obtained from 33 patients with acute myelogenous leukemia (AML). Leukemic colony formation was found in approximately 70 to 80% of the patients in the presence of at least one of the above CSFs. Although IL-11 alone did not support L-CFU, the growth of these progenitors in the presence of other cytokines was enhanced by IL-11 in 16 out of 33 patients and it showed a synergistic action with G-CSF in 12 of them. This synergistic action occurred in seven out of nine M5 patients (French-American-British (FAB) classification). A single cell clone-sorting experiment clearly demonstrated that this synergistic effect was operative at the single progenitor cell level. The number of leukemic cells proliferating in the presence of G-CSF+IL-11 was significantly higher than in the presence of G-CSF alone, suggesting that IL-11 recruited dormant leukemic progenitors into the cell cycle. Flow cytometric analysis revealed that all types of AML blast cells (M0 approximately M6) ubiquitously expressed gp130, although the level of expression was significantly higher in M5 cells. In contrast, expression of the IL-11 receptor alpha chain (IL-11Ralpha) varied between FAB types. Blast cells obtained from M1, M3 and M5 patients showed higher levels of expression, with M5 cells showing the strongest expression. Interestingly, the leukemic progenitor cells for which proliferation was synergistically enhanced by IL-11 had significantly higher expression of both IL-11Ralpha and gp130. These results suggest that administration of IL-11 in vivo may stimulate the proliferation of leukemic progenitor cells, particularly M5 cells, in the presence of G-CSF, and that the responsiveness of L-CFU to IL-11 may be predicted by a simple receptor assay.
Department of Hygiene, Kyoto Prefectural University of Medicine, Kyoto, Japan.
T
T
Kimura
H
H
Sakabe
H
H
Minamiguchi
H
H
Fujiki
T
T
Abe
H
H
Kaneko
S
S
Yokota
H
H
Nakagawa
H
H
Fujii
H
H
Tamaki
H
H
Ogawa
H
H
Sugiyama
Y
Y
Sonoda
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis*; D002455:Cell Division / Q000187:drug effects; D050822:Cytokine Receptor gp130; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D017370:Interleukin-11 / Q000627:therapeutic use*; D053703:Interleukin-11 Receptor alpha Subunit; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis*; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis*; D018123:Receptors, Interleukin / Q000737:chemistry*; D053702:Receptors, Interleukin-11; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D015703:Antigens, CD; C508428:IL11RA protein, human; C494199:IL6ST protein, human; D017370:Interleukin-11; D053703:Interleukin-11 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D053702:Receptors, Interleukin-11; D050822:Cytokine Receptor gp130