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Published on: June 15, 2016
Checkpoint kinase 1 (CHK1) protein and mRNA expression is downregulated in aggressive variants of human lymphoid
1Laboratory of Pathology, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Villaroel 170, 08036 Barcelona, Spain.
Abstract:
CHK1: gene encodes for a serine/threonine kinase involved in the regulation of cell cycle progression and DNA damage checkpoints. To determine the role of CHK1 in the pathogenesis of lymphoid neoplasms and its relationship to other DNA damage response genes, we have analyzed the gene status, protein, and mRNA expression in a series of tumors and nonneoplastic lymphoid tissues. CHK1 protein and mRNA expression levels were very low in both reactive tissues and resting lymphoid cells, whereas tumor samples showed a variable pattern of expression related to their proliferative activity. However, seven aggressive tumors showed a dissociate pattern of extremely low or negative protein expression in spite of a high proliferative activity. Four of these tumors were diffuse large B-cell lymphomas (DLCLs) with concordant reduced levels of mRNA, whereas one blastoid mantle cell lymphoma (B-MCL) and two DLCLs had relatively normal levels of mRNA. No gene mutations, deletions, or hypermethylation of the promoter region were detected in any of these cases. In all these tumors ATM, CHK2, and p53 genes were wild type. These findings suggest that CHK1 inactivation in NHLs occurs by loss of protein expression in a subset of aggressive variants alternatively to ATM, CHK2, and p53 alterations.
Insights
Checkpoint kinase 1 (CHK1) protein loss occurs in aggressive non-Hodgkin lymphomas (NHLs). This inactivation, independent of gene mutations, suggests CHK1 plays a role in NHL pathogenesis.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Checkpoint kinase 1 (CHK1) is a serine/threonine kinase crucial for cell cycle regulation and DNA damage response.
- Understanding CHK1's role in lymphoid neoplasms is vital for comprehending their pathogenesis.
Purpose of the Study:
- To investigate the role of CHK1 in lymphoid neoplasms.
- To analyze CHK1's relationship with other DNA damage response genes in these cancers.
Main Methods:
- Analysis of CHK1 gene status, protein, and mRNA expression in tumor and nonneoplastic lymphoid tissues.
- Assessment of ATM, CHK2, and p53 gene status.
Main Results:
- Low CHK1 protein and mRNA in reactive tissues and resting cells.
- Variable CHK1 expression in tumors correlated with proliferation.
- Seven aggressive tumors showed low CHK1 protein despite high proliferation, with four DLCLs having reduced mRNA.
- No CHK1 gene mutations, deletions, or promoter hypermethylation were found.
- ATM, CHK2, and p53 were wild type in all analyzed tumors.
Conclusions:
- CHK1 inactivation in aggressive non-Hodgkin lymphomas (NHLs) can occur via loss of protein expression.
- This inactivation is independent of ATM, CHK2, and p53 alterations.
- Loss of CHK1 expression represents an alternative mechanism in NHL pathogenesis.
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