Cross-Sectional Study: Associations of A20 and Cezanne with Leukocyte Accumulation in B-Cell Acute Lymphoblastic Leukemia

TL;DR

This study explores how genetic variants in A20 and Cezanne genes are linked to increased leukocyte accumulation and worse outcomes in patients with B-cell acute lymphoblastic leukemia.

Contribution

The study identifies specific A20 and Cezanne gene variants associated with leukocyte expansion and poor prognosis in B-ALL patients.

Findings

A20 p.P348L and Cezanne rs1230581026 variants are linked to lower gene expression and higher leukocyte counts in B-ALL patients.

Carriers of these variants show increased CD20+, HLA DR+, and CD38+ cells, along with elevated neutrophil and lymphocyte counts.

Age-related increases in TNF-α levels are observed in patients with the Cezanne variant.

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.

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