Down-regulation of interleukin-3/granulocyte-macrophage colony-stimulating factor receptor b-chain in BCR-ABL1 human leukemic cells: association with loss of cytokine-mediated Stat-5 activation and protection from apoptosis after BCR-ABL inhibition

Several signaling cascades are engaged by expression of the p210 bcr-abl tyrosine kinase, and evidence suggests that these signals drive leukemogenesis. In this report, signaling pathways were examined and compared between cells derived from leukemic patients and cells expressing a bcr-abl construct (MBA). The effects of acute inhibition of bcr-abl with STI-571 on these signals and the survival of bcr-abl–expressing cells were also evaluated. Expression of bcrabl in interleukin-3 (IL-3)/granulocytemacrophage colony-stimulating factor (GM-CSF)–dependent Mo7e cells (MBA) resulted in growth factor independence, constitutive activation of Stat-5 phosphorylation, engagement of mitogen-activated protein (MAP) kinase signals, and increased expression of PTP1B and bcl-xL. STI-571 inhibited cell growth and induced apoptosis in bcr-abl–expressing cells (MBA, K562, BV-173, KBM5) but not in bcr-abl2 tumor cells (Mo7e, KG-1, ME180, Daudi). STI-571–mediated apoptosis correlated with the inhibition of Stat-5 and MAP kinase activation and a reduction in overexpressed bcl-xL but not in PTP1B. Inhibitor had no effect on IL-3/GMCSF–dependent Mo7e cell signaling and did not prevent activation of the other Jak/Stat pathways (interferon a, IL-3/GMCSF). However, neither IL-3 nor GM-CSF could reactivate Stat-5 after the STI-571– mediated inhibition of bcr-abl. Expression of the common b-chain of the IL-3/ GM-CSF receptor was down-regulated in Stat-5–activated myeloid leukemic cells, suppressing IL-3/GM-CSF signal transduction and the ability of these cytokines to provide apoptotic protection. These studies suggest that bcr-abl activates cytokine-independent mechanisms of survival while inactivating intrinsic cytokine signaling cascades, making bcr-abl1 myeloid cells vulnerable to apoptosis after bcr-abl inactivation. (Blood. 2001;97:2846-2853)