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A Chromatin Immunoprecipitation Assay to Identify Novel NFAT2 Target Genes in Chronic Lymphocytic Leukemia
Published on: December 4, 2018
CHK2-decreased protein expression and infrequent genetic alterations mainly occur in aggressive types of non-Hodgkin
Frederic Tort1, Silvia Hernàndez, Silvia Beà
1Laboratory of Pathology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain.
Abstract:
The CHK2 gene codifies for a serine/threonine kinase that plays a central role in DNA damage response pathways. To determine the potential role of CHK2 alterations in the pathogenesis of lymphoid neoplasms we have examined the gene status, protein, and mRNA expression in a series of tumors and nonneoplastic lymphoid samples. A heterozygous Ile157Thr substitution, also present in the germ line of the patient, was detected in a blastoid mantle cell lymphoma (MCL). CHK2 protein and mRNA expression levels were similar in all types of lymphomas and reactive samples, and these levels were independent of the proliferative activity of the tumors. However, 5 tumors, one typical MCL, 2 blastoid MCLs, and 2 large cell lymphomas, showed marked loss of protein expression, including 2 samples with complete absence of CHK2 protein. These 2 lymphomas showed the highest number of chromosomal imbalances detected by comparative genomic hybridization in the whole series of cases. However, no mutations, deletions, or hypermethylation of the promoter region were identified in any of these tumors. mRNA levels were similar in cases with low and normal protein expression, suggesting a posttranscriptional regulation of the protein in these tumors. CHK2 gene and protein alterations were not related to p53 and ATM gene status. In conclusion, CHK2 alterations are uncommon in malignant lymphomas but occur in a subset of aggressive tumors independently of p53 or ATM alterations. The high number of chromosomal imbalances in tumors with complete absence of CHK2 protein suggests a role of this gene in chromosomal instability in human lymphomas.
Insights
Checkpoint kinase 2 (CHK2) alterations are infrequent in lymphoid neoplasms but observed in aggressive tumors. Loss of CHK2 protein expression correlates with chromosomal instability, suggesting a role in lymphoma pathogenesis.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- The CHK2 gene encodes a kinase crucial for DNA damage response.
- Understanding CHK2's role in lymphoid neoplasms is important for cancer research.
Purpose of the Study:
- To investigate CHK2 gene and protein alterations in lymphoid neoplasms.
- To determine the association between CHK2 status and tumor characteristics.
Main Methods:
- Examined CHK2 gene status, protein, and mRNA expression in tumor and non-neoplastic lymphoid samples.
- Utilized comparative genomic hybridization to assess chromosomal imbalances.
Main Results:
- A heterozygous Ile157Thr substitution was found in one blastoid mantle cell lymphoma.
- Marked loss of CHK2 protein expression occurred in 5 tumors, with complete absence in 2 lymphomas.
- Tumors lacking CHK2 protein showed the highest chromosomal instability.
- No mutations, deletions, or promoter hypermethylation were identified in these tumors.
Conclusions:
- CHK2 alterations are uncommon in malignant lymphomas but present in aggressive subtypes.
- Loss of CHK2 protein may contribute to chromosomal instability in lymphomas.
- Posttranscriptional regulation might influence CHK2 protein levels.
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