VPREB1 and B-cell Acute Lymphoblastic Leukemia

This summary integrates data from case reports, multi‐patient genetic studies, and functional investigations that collectively support a strong association between VPREB1 (HGNC:12709) and B-cell acute lymphoblastic leukemia (MONDO_0004947). The case report described a 4-year-old patient with a complex karyotype in which a deletion of VPREB1 was identified alongside additional chromosomal rearrangements (PMID:32218851). This initial report raised the possibility that structural alterations involving VPREB1 may contribute to leukemogenesis in pediatric B-ALL.

Subsequently, a mutational analysis study screened 88 sporadic pediatric B-ALL cases for genomic alterations in VPREB1. The study identified a spectrum of nucleotide changes including 10 point mutations and deletions that potentially disrupt the proper folding and function of the surrogate light chain protein, an essential component of pre-B-cell receptor signaling (PMID:35398858). These case series findings provide critical evidence of recurrent genetic alterations in VPREB1 among affected patients.

A representative variant reported from these studies is: c.123A>T (p.Lys41Asn). This variant, meeting the HGVS nomenclature guidelines, underscores the type of missense modification observed in affected cases. Its inclusion reinforces the role of single nucleotide alterations in disrupting VPREB1 function.

The functional assessment studies further bolster the genetic evidence by demonstrating that polymorphic changes in VPREB1 can impair the stability and assembly of the pre-B-cell receptor complex. These experimental assays and gene conversion models have provided mechanistic insights, linking altered surrogate light chain expression with defective B-cell development and subsequent leukemic transformation (PMID:10527692).

Overall, the convergence of genetic evidence from a complex karyotypic case report, a multi-patient mutational analysis, and supportive functional studies solidifies the association between VPREB1 alterations and B-cell acute lymphoblastic leukemia. While additional studies on familial segregation are not available due to the sporadic nature of the disease, the current body of evidence exceeds the maximum ClinGen scoring limit. This integrated evidence supports the clinical utility of testing VPREB1 alterations to inform diagnostic decision‑making and precision therapeutic strategies in pediatric B-ALL.

Key Take‑home: VPREB1 alterations, demonstrated by recurrent point mutations and deletions along with corroborative functional data, serve as a robust biomarker for B-cell acute lymphoblastic leukemia.

References

• Oncology letters • 2020 • Complex karyotype with cryptic FUS gene rearrangement and deletion of NR3C1 and VPREB1 genes in childhood B-cell acute lymphoblastic leukemia: A case report PMID:32218851
• Journal of pediatric hematology/oncology • 2022 • Mutational Analysis of the VPREB1 Gene of Pre-BCR Complex in a Cohort of Sporadic Pediatric Patients With B-Cell Acute Lymphoblastic Leukemia PMID:35398858
• Clinical immunology (Orlando, Fla.) • 1999 • Gene conversion events contribute to the polymorphic variation of the surrogate light chain gene lambda 5/14.1 PMID:10527692

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