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Optimal IL-7R-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on CK2 activity

Melão, A; Spit, M; Cardoso, BA; Barata, JT; (2016) Optimal IL-7R-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on CK2 activity. Haematologica , 101 pp. 1368-1379. 10.3324/haematol.2015.141143. Green open access

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Abstract

Interleukin-7 and IL7R are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/IL7R-mediated signaling promotes leukemogenesis. Protein kinase CK2 is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Here, we show that while interleukin-7 had a minor but significant positive effect on CK2 activity in leukemia T-cells, CK2 activity was mandatory for optimal interleukin-7/IL7R-mediated signaling. CK2 pharmacological inhibition impaired STAT5 and PI3K/Akt pathway activation triggered by interleukin-7 or by mutational activation of IL7R. By contrast, forced expression of CK2 augmented interleukin-7 signaling in HEK293T cells reconstituted with the IL7R machinery. CK2 inactivation prevented interleukin-7-induced Bcl-2 upregulation, maintenance of mitochondrial homeostasis and viability of T-cell acute lymphoblastic leukemia cell lines and primary leukemia cells collected from patients at diagnosis. CK2 inhibition further abrogated interleukin-7-mediated cell growth and upregulation of the transferrin receptor, and blocked cyclin A and E upregulation and cell cycle progression. Notably, CK2 was also required for the viability of mutant IL7R-expressing leukemia T-cells. Overall, our study identifies CK2 as a major player in the effects of interleukin-7 and IL7R in T-cell acute lymphoblastic leukemia. This further highlights the potential relevance of targeting CK2 in this malignancy.

Type: Article
Title: Optimal IL-7R-mediated signaling, cell cycle progression and viability of T-cell acute lymphoblastic leukemia cells rely on CK2 activity
Open access status: An open access version is available from UCL Discovery
DOI: 10.3324/haematol.2015.141143
Publisher version: http://dx.doi.org/10.3324/haematol.2015.141143
Language: English
Additional information: Copyright© 2017 Ferrata Storti Foundation.
Keywords: CK2, IL-7 and IL-7R, Pediatric Acute Lymphoblastic Leukemia, T-ALL, signaling therapeutics
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/1507773
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