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.
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.
Malinge
S
S
EMI 0210, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris, France.
Monni
R
R
Bernard
O
O
Penard-Lacronique
V
V
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein; D053614:Janus Kinase 2
D051550:I-kappa B Kinase; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; C426234:TEL-ABL fusion protein, human; D000097764:ETS Translocation Variant 6 Protein; C491568:TEL-JAK2 fusion protein, mouse; D053614:Janus Kinase 2; C497971:Flt3 protein, mouse; C496559:CHUK protein, human