CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress.
In: Oncogene, Jg. 34 (2015-06-04), Heft 23, S. 2978-2990
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Checkpoint kinase 1 (CHK1) is a key component of the ATR (ataxia telangiectasia-mutated and Rad3-related)-dependent DNA damage response pathway that protect cells from replication stress, a cell intrinsic phenomenon enhanced by oncogenic transformation. Here, we show that CHK1 is overexpressed and hyperactivated in T-cell acute lymphoblastic leukemia (T-ALL). CHEK1 mRNA is highly abundant in patients of the proliferative T-ALL subgroup and leukemia cells exhibit constitutively elevated levels of the replication stress marker phospho-RPA32 and the DNA damage marker γH2AX. Importantly, pharmacologic inhibition of CHK1 using PF-004777736 or CHK1 short hairpin RNA-mediated silencing impairs T-ALL cell proliferation and viability. CHK1 inactivation results in the accumulation of cells with incompletely replicated DNA, ensuing DNA damage, ATM/CHK2 activation and subsequent ATM- and caspase-3-dependent apoptosis. In contrast to normal thymocytes, primary T-ALL cells are sensitive to therapeutic doses of PF-004777736, even in the presence of stromal or interleukin-7 survival signals. Moreover, CHK1 inhibition significantly delays in vivo growth of xenotransplanted T-ALL tumors. We conclude that CHK1 is critical for T-ALL proliferation and viability by downmodulating replication stress and preventing ATM/caspase-3-dependent cell death. Pharmacologic inhibition of CHK1 may be a promising therapeutic alternative for T-ALL treatment. [ABSTRACT FROM AUTHOR]
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CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress.
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Autor/in / Beteiligte Person: | Sarmento, L M ; Póvoa, V ; Nascimento, R ; Real, G ; Antunes, I ; Martins, L R ; Moita, C ; Alves, P M ; Abecasis, M ; Moita, L F ; Parkhouse, R M E ; Meijerink, J P P ; Barata, J T |
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Zeitschrift: | Oncogene, Jg. 34 (2015-06-04), Heft 23, S. 2978-2990 |
Veröffentlichung: | 2015 |
Medientyp: | academicJournal |
ISSN: | 0950-9232 (print) |
DOI: | 10.1038/onc.2014.248 |
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