Activation of the NF-kappaB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKalpha

Abstract

Abnormal activation of tyrosine kinases and of signaling pathways they control plays a critical role in the neoplastic process of human hematopoietic malignancy. The nuclear factor-kappaB (NF-kappaB) pathway is one of the signalings activated by the TEL-Jak2 and TEL-Abl oncoproteins and required for their antiapoptotic activity. To define the signal relay responsible for this activation, we used mouse embryonic fibroblast (MEF) cells and observed that TEL-Jak2- and TEL-Abl-mediated NF-kappaB induction was abolished in cells lacking the IkappaB kinase (IKK)alpha but not in IKKbeta(-/-) cells. Similar observations were performed with oncogenic forms of the FMS-like tyrosine kinase 3 (Flt-3) involved in the pathogenesis of one-third of acute myeloid leukemias. Rescue of TEL-Jak2-mediated NF-kappaB activation was obtained with a kinase-proficient form of IKKalpha in IKKalpha(-/-) MEF. Hematopoietic cells transformed by TEL-Jak2 and TEL-Abl showed sustained IKKalpha activity without promotion of NF-kappaB2/p100 processing, generally associated to IKKalpha functions. Furthermore, IAP1, IAP2 and XIAP, which are central regulators of the NF-kappaB-mediated survival pathway, were highly expressed in cells transformed by these oncoproteins. Our results indicate that these oncogenic tyrosine kinases preferentially use an IKKalpha-dependent mechanism to induce a persistent NF-kappaB activity and allow the production of antiapoptotic effectors that participate to their leukemogenic properties.