A recent study involving children with hematologic malignancies has suggested that mutations in a portion of a cohesin gene known as RAD21 may have relevance to pediatric lymphoblastic leukemia or lymphoma. Findings of the study were reported in the International Journal of Molecular Sciences.
“The cohesin complex is one of the most essential keepers of genome stability, ensuring proper cell development and proliferation,” the researchers who performed the study explained in their report. A component of the cohesin complex that is important to its structure is the RAD21 protein, which is encoded by the RAD21 gene.
Mutations in RAD21 or other elements of the cohesin complex have been seen in some cases of children with acute lymphoblastic leukemia (ALL) or precursor B-cell ALL, the researchers indicated. However, research on possible connections between mutations related to the cohesin complex and childhood leukemia or cancer has been limited.
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In this study, patients in childhood cancer cohorts underwent DNA extraction for a series of analyses including whole exome sequencing, gene expression, and gene ontology approaches, and others. Data based on human bone marrow without leukemia or lymphoma and from adults with cancer were also analyzed for some comparisons.
A total of 482 pediatric patients with cancer were evaluated from across multiple cohorts. Overall, 3 children with lymphoblastic leukemia or lymphoma who were in 3 separate cohorts of patients with cancer showed a mutational pattern of interest, which involved germline mutations of functional significance in the RAD21 gene at amino acid position 298 (p.P298S/A).
Immunoprecipitation assays indicated that the RAD21 p.P298S/A variants appeared not to disrupt cohesin complex formation. Microarray analysis revealed that these variants were associated with significant up- or downregulation of 83 other genes, with gene ontology analyses suggesting many were genes related to the p53 signaling pathway.
Additionally, fibroblast cell lines containing RAD21 p.P298S or p.P298A showed G2/M cell cycle arrest when subjected to ionizing irradiation, or S/G2/M cell cycle arrest with mitomycin-C treatment, to significantly higher levels than seen with a wild-type control. RAD21 p.298S/A variants were also associated with downregulated RAD21 expression, compared with expression in wild type.
Analyses involving human bone marrow without leukemia or lymphoma data indicated that RAD21 expression was highest in actively dividing cells in G2/M or S phases, compared with G1. RNA-sequencing analyses showed differential expression patterns for cohesin complex genes during B-cell lineage specification.
The RAD21 p.P298S/A variants appeared to be enriched in pediatric cancers, compared with adult cancers (P =.018). However, an analysis of data involving pediatric patients with treatment-refractory leukemia and lymphoma showed no enrichment of RAD21 p.P298S/A, suggesting an association was not seen between these variants and therapy response.
“Taken together, in addition to RAD21 germline and somatic loss-of-function variants that result in cohesinopathies and predominantly myeloid cancers, respectively, our data propose a third category of RAD21 variants that mediate germline predisposition to lymphoblastic malignancies in childhood,” the researchers concluded in their report.
Reference
Schedel A, Friedrich UA, Morcos MNF, et al. Recurrent germline variant in RAD21 predisposes children to lymphoblastic leukemia or lymphoma. Int J Mol Sci. 2022;23(9):5174. doi:10.3390/ijms23095174
