Mechanisms of Bcr-Abl-mediated NF-κB/Rel activation

Bcr-Abl constitutes a deregulated tyrosine kinase involved in the pathogenesis of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL). Although activation of the transcription factor NF-κB/Rel has been demonstrated, mechanisms of NF-κB/Rel activation by Bcr-Abl remain obscure. In this paper we demonstrate activation of NF-κB/Rel by Bcr-Abl and for the first time by v-Abl. Furthermore, we investigated mechanisms of NF-κB/Rel induction by Bcr-Abl and v-Abl. Both Bcr-Abl and v-Abl induced NF-κB/Rel DNA binding in Ba/F3 cells. DNA binding was a result of nuclear translocation of p65/RelA, whereas p65/RelA expression was unaffected. Nuclear translocation of p65/RelA is at least partially due to increased IκBα degradation, which is independent of IκB kinase (IKK) activity. IKK activity is not deregulated by Bcr-Abl and v-Abl. NF-κB/Rel transactivation was dependent on abl kinase activity but independent of Grb2 and Grb10 binding tobcr sequences. In addition, NF-κB/Rel activation was dependent on Ras activity. Primary CML blasts showed constitutive p65/RelA NF-κB/Rel DNA binding activity. Thus NF-κB/Rel represents a potential target for molecular therapies in CML.