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

Oncogene volume 25, pages 3589–3597 (2006)Cite this article

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-κB (NF-κB) 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-κB induction was abolished in cells lacking the IκB kinase (IKK)α but not in IKKβ−/− 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-κB activation was obtained with a kinase-proficient form of IKKα in IKKα−/− MEF. Hematopoietic cells transformed by TEL-Jak2 and TEL-Abl showed sustained IKKα activity without promotion of NF-κB2/p100 processing, generally associated to IKKα functions. Furthermore, IAP1, IAP2 and XIAP, which are central regulators of the NF-κB-mediated survival pathway, were highly expressed in cells transformed by these oncoproteins. Our results indicate that these oncogenic tyrosine kinases preferentially use an IKKα-dependent mechanism to induce a persistent NF-κB activity and allow the production of antiapoptotic effectors that participate to their leukemogenic properties.

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Acknowledgements

We are grateful to R Weil and V Baud for helpful discussion and to E Delabesse and D Baudry-Bluteau for their help with the real-time PCRs. This work was supported in part by grants from the Ligue Nationale Contre le Cancer (LNCC-équipe labelisée). SM is supported by a Ministère de l'Education Nationale, de la Recherche et des Technologies (MENRT) fellowship.

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  1. EMI 0210, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris, France

    S Malinge, O Bernard & V Penard-Lacronique

  2. INSERM U528, Section de recherche, Institut Curie, 26 rue d'Ulm, Paris, France

    R Monni

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  1. S Malinge
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Correspondence to V Penard-Lacronique.

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Malinge, S., Monni, R., Bernard, O. et al. Activation of the NF-κB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKα. Oncogene 25, 3589–3597 (2006). https://doi.org/10.1038/sj.onc.1209390

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