JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells

Cytokines of the interleukin 6 (IL-6) family, which activates the signal tr ansducer gp130, are major survival and growth factors for human multiple my eloma (MM) cells. The signal transduction of gp130 involves the Janus tyros ine kinases (JAK) JAK1, JAK2 and Tyk2 and then the downstream effectors com prising the signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways. We evaluated the effects of the JAK2 inhibitor tyrphostin AG490 on MM cells. We found that AG490 sup pressed cell proliferation and induced apoptosis in IL-6-dependent MM cell lines. JAK2 kinase activity, ERK2 and STAT3 phosphorylation were inhibited. These results suggest that the chemical blocking of the gp130 signalling p athway at the JAK level could be a relevant therapeutic approach to MM.