Associação Portuguesa de Investigação em Cancro
A cinase CK2 é essencial para a proliferação de células T leucémicas induzida pela interleucina-7
A cinase CK2 é essencial para a proliferação de células T leucémicas induzida pela interleucina-7
Num estudo publicado recentemente, os investigadores demontraram que duas vias oncogénicas, envolvidas em leucemia linfoblástica aguda de células T (LLA-T), se interligam: cinase CK2 interage fisicamente com o receptor da interleucina-7 (IL-7R) e é indispensável para a activação máxima da transdução de sinal mediada pela ligação da interleucina-7 ao IL-7R nas células LLA-T. Na ausência de activação de CK2, a viabilidade, progressão no ciclo celular e, em última análise, proliferação das células leucémicas em resposta a IL-7 deixam de ocorrer. Inibidores farmacológicos de CK2 poderão ter um impacto terapêutico alargado em LLA-T.
Autores e Afiliações:
Alice Melão, Maureen Spit, Bruno A. Cardoso, João T. Barata
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
Abstract:
Interleukin 7 (IL-7) and its receptor (IL-7R) are essential for normal T-cell development and homeostasis, whereas excessive IL-7/IL-7R-mediated signaling promotes leukemogenesis. Protein kinase CK2 is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia (T-ALL). Here, we show that while IL-7 had a minor but significant positive effect on CK2 activity in T-ALL cells, CK2 activity was mandatory for optimal IL-7/IL-7R-mediated signaling. CK2 pharmacological inhibition abrogated STAT5 and PI3K/Akt pathway activation triggered by IL-7 or by mutational activation of IL-7Rα. By contrast, forced expression of CK2 augmented IL-7 signaling in HEK293T cells reconstituted with the IL-7R machinery. CK2 inactivation prevented IL-7-induced Bcl-2 upregulation, maintenance of mitochondrial homeostasis and viability of T-ALL cell lines and primary leukemia cells collected from patients at diagnosis. CK2 inhibition further abrogated IL-7-mediated cell growth and upregulation of the transferrin receptor, and blocked cyclin A and E upregulation and T-ALL cell cycle progression. Notably, CK2 was also required for the viability of mutant IL-7R-expressing T-ALL cells. Overall, our study identifies CK2 as a major player in the effects of IL-7 and IL-7R in T-ALL. This further highlights the potential relevance of targeting CK2 in this malignancy.
Revista: Haematologica
Link: http://www.haematologica.org/content/101/11/1368.long