CHK1 overexpression in T-cell acute lymphoblastic leukemia is essential for proliferation and survival by preventing excessive replication stress

• Published in: Oncogene 2015-06, Vol.34 (23), p.2978-2990
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/21; 13/31; 13/44; 13/95; 14/35; 14/5; 14/63; 38/61; 38/89; 38/90; 631/67/1059/602; 631/67/1990/283/2125; 631/67/395; 631/80/304; 64/60; 82/29; 96/34; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Animals; Apoptosis; Ataxia telangiectasia; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins - metabolism; Benzodiazepinones - administration & dosage; Benzodiazepinones - pharmacology; Caspase 3 - metabolism; Caspase-3; Cell Biology; Cell Cycle; Cell death; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell Survival; Checkpoint Kinase 1; CHK1 protein; Cytokines; Deoxyribonucleic acid; Development and progression; DNA; DNA Damage; DNA Replication; Enzyme regulation; Gene Knockdown Techniques; Genetic aspects; Health aspects; Human Genetics; Humans; Interleukin 7; Internal Medicine; Kinases; Leukemia; Lymphatic leukemia; Lymphocytes T; Medicine; Medicine & Public Health; Mice; mRNA; Neoplasm Transplantation; Oncology; original-article; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein Kinases - genetics; Protein Kinases - metabolism; Pyrazoles - administration & dosage; Pyrazoles - pharmacology; Replication; RNA-mediated interference; Thymocytes; Thymocytes - metabolism; Tumors; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.248

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.