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Published on: July 20, 2016
Cross-Sectional Study: Associations of A20 and Cezanne with Leukocyte Accumulation in B-Cell Acute Lymphoblastic
Le Thuy Ha1, Nguyen Hoang Giang2,3, Nguyen Linh Toan4
1103 Military Hospital, Vietnam Military Medical University, 261 Phung Hung, Ha Dong, Hanoi 10000, Vietnam.
Insights
Genetic variants in A20 and Cezanne genes are linked to increased leukocyte counts and poor outcomes in B-cell acute lymphoblastic leukemia (B-ALL). These findings highlight potential new biomarkers for B-ALL progression.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Acute lymphoblastic leukemia (ALL) is a cancer of immature lymphoid cells.
- B-cell ALL (B-ALL) involves lymphoblasts from the B-cell lineage.
- Deubiquitinase genes A20, CYLD, and Cezanne regulate inflammation and tumor growth; elevated TNF-α correlates with poor ALL outcomes.
Purpose of the Study:
- To investigate the association between A20, CYLD, and Cezanne genes and leukocyte accumulation in B-ALL.
- To identify genetic variants in A20 and Cezanne and their impact on B-ALL.
- To explore the relationship between these variants, inflammatory markers, and clinical outcomes in B-ALL.
Main Methods:
- Gene expression profiling using quantitative PCR.
- Gene polymorphism analysis via direct DNA sequencing.
- Immunophenotyping by flow cytometry and cytokine analysis using ELISA on blood samples from B-ALL patients and healthy controls.
Main Results:
- Identified six nucleotide changes in A20 exon 7 and three variants in Cezanne intron 10.
- B-ALL patients with A20 p.P348L and Cezanne rs1230581026 variants showed higher frequencies and lower gene expression.
- Carriers of these variants had increased CD20+, HLA-DR+, CD38+ cells, neutrophils, basophils, monocytes, and lymphocytes, along with elevated TNF-α levels.
Conclusions:
- A20 p.P348L and Cezanne rs1230581026 variants are associated with reduced A20/Cezanne expression in B-ALL.
- These variants correlate with leukocyte expansion and poorer outcomes in B-ALL patients.
- The findings suggest these variants as potential prognostic markers for B-ALL.
Abstract:
Background and Objectives: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the aberrant proliferation of immature lymphoid cells. Lymphoblasts derived from the B-cell lymphoid lineage are identified as B-ALL. A20, CYLD and Cezanne are deubiquitinase genes that inhibit inflammatory response and tumor progression. Age-related increases in tumor necrosis factor (TNF)-α are associated with poor outcomes in ALL. Little is known about the associations of A20, CYLD and Cezanne with leukocyte accumulation in B-ALL. Materials and Methods: Blood samples of 147 patients with B-ALL and 144 healthy subjects were examined. Gene expression profiles were determined by quantitative PCR, gene polymorphisms by direct DNA sequencing, immunophenotype by flow cytometry and secretion of inflammatory cytokines by an ELISA. Results: Genetic analysis of the A20 gene identified six nucleotide changes in exon 7. Sequencing of the Cezanne gene identified three variants in intron 10. The results indicated that B-ALL patients carrying the A20 p.P348L and Cezanne rs1230581026 variants had higher variant frequencies and lower expression levels than healthy controls. Importantly, carriers of the A20 p.P348L variant had a higher numbers of CD20+ and HLA DR+ cells than those with a normal genotype, and carriers of the Cezanne rs1230581026 variant had increases in neutrophil, basophil, monocyte, lymphocyte, and CD38+ cell counts as well as age-related increases in the levels of TNF-α. Conclusions: The results indicate that the A20 p.P348L and Cezanne rs1230581026 variants are associated with low expression levels of A20/Cezanne, leukocyte expansion and poor outcomes in B-ALL patients.
