Interleukin (IL)-15 induces survival and proliferation of the growth factor-dependent acute myeloid leukemia M-07e through the IL-2 receptor beta/gamma.
We have analyzed the effects of IL-15, a growth factor with IL-2-like properties produced by dendritic and stromal cells, on 3 GM-CSF/IL-3-dependent AML cell lines: M-07e, UT-7 and TF-1. M-07e cells proliferated in response to IL-15, while UT-7 and TF-1 cells failed to respond. In addition, IL-15 supported long-term proliferation of M-07e cells, thus allowing selection of a subline (M-07SB), which displayed an enhanced sensitivity to IL-15. M-07e and M-07SB cells undergo apoptosis following 48-hr growth factor (GM-CSF or IL-15) starvation, as detected by cytofluorimetric analysis and DNA laddering. IL-15 (20 ng/ml) prevented apoptosis in both cell lines. M-07e and M-07SB expressed IL-2R beta, IL-2R gamma, Jak-1 and Jak-3 mRNA, while IL-15R alpha mRNA was undetectable. In contrast, IL-15R alpha was expressed in UT-7 and TF-1 cells, which lacked expression of IL-2R beta mRNA and, in the case of UT-7, also of Jak-3 mRNA. Accordingly, surface IL-2R beta protein was identified only in M-07e and M-07SB cells, by indirect immunofluorescence, while no expression of IL-2R alpha and IL-15R alpha was detected. Anti-IL-2R beta antibodies (10 microg/ml) efficiently blocked (90% inhibition) the proliferation and the anti-apoptotic effect induced by IL-15, while anti-GM-CSFR alpha antibodies had no effect. Anti-IL-2R gamma antibodies were less efficient at proliferation inhibition but synergized with suboptimal concentrations of anti-IL-2R beta antibodies. Our data suggest a role of IL-15 as an anti-apoptotic and mitogenic growth factor for a subset of myeloid leukemias expressing a functional IL-2R beta/gamma complex.
Meazza
R
R
Istituto Nazionale per la Ricerca sul Cancro, Centro di Biotecnologie Avanzate, Genoa, Italy.
Basso
S
S
Gaggero
A
A
Detotero
D
D
Trentin
L
L
Pereno
R
R
Azzarone
B
B
Ferrini
S
S
D000208:Acute Disease; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism / Q000494:pharmacology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D007951:Leukemia, Myeloid / Q000473:pathology*; D046911:Macromolecular Substances; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*
D006133:Growth Substances; C508024:IL15RA protein, human; D019409:Interleukin-15; D046911:Macromolecular Substances; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2