CASE REPORT article
Front. Oncol.
Sec. Hematologic Malignancies
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1630715
A Familial Hematological Pedigree Reveals VHL Germline Mutation as a Principal Predisposition Factor with Additional Mutations Modulating Phenotypic Heterogeneity
Provisionally accepted
- 1Department of Hematology, Lanzhou University Second Hospital, Lanzhou, China
- 2Lanzhou University Second Hospital, Lanzhuo, China
- 3The Second Clinical Medicine School, Lanzhou University, Lanzhou, China
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Background: VHL germline mutations are classically associated with von Hippel-Lindau syndrome, but their role in hematological malignancies remains underexplored.We analyzed a pedigree with acute myeloid leukemia (AML) proband and two offspring: primary immune thrombocytopenia (ITP) and acute T-cell lymphoblastic leukemia (T-ALL) via targeted sequencing and familial validation. Results: Genetic analysis revealed: (1) the proband carried concurrent VHL, ASXL3, and CCR7 germline mutations along with acquired BCOR/NF1 variants; (2) the ITP-affected offspring inherited ASXL3/CCR7 mutations only; and (3) the T-ALL case exhibited solely the VHL mutation. Acquired mutations (e.g., BCOR/NF1) in the proband suggest a 'two-hit' model for leukemogenesis.This study identifies VHL as the principal predisposing mutation in a familial hematologic malignancy pedigree presenting with heterogeneous phenotypes , where ASXL3/CCR7 variants may serve as phenotypic modifiers. These findings advocate for genotype-driven surveillance strategies in familial hematological disorders.
Keywords: VHL, ASXL3, CCR7, germline mutation, familial hematological disease, genetic
Received: 18 May 2025; Accepted: 07 Jul 2025.
Copyright: © 2025 Chen, Hu, Ma, Zhang, Yang and Zeng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Huiling Chen, Department of Hematology, Lanzhou University Second Hospital, Lanzhou, China
Pengyun Zeng, Lanzhou University Second Hospital, Lanzhuo, China
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