Chen HuiLing, Hu Wanli, Ma Chengcheng, Zhang Miaomiao, Yang Fuhua, Zeng Pengyun
Department of Hematology, Lanzhou University Second Hospital, Lanzhou, Gansu, China.
The Second Clinical Medicine School, Lanzhou University, Lanzhou, Gansu, China.
Front Oncol. 2025 Jul 29;15:1630715. doi: 10.3389/fonc.2025.1630715. eCollection 2025.
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.
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.
VHL基因种系突变通常与冯·希佩尔-林道综合征相关，但其在血液系统恶性肿瘤中的作用仍未得到充分研究。
我们通过靶向测序和家族验证分析了一个家系，该家系的先证者患有急性髓系白血病（AML），两个后代分别患有原发性免疫性血小板减少症（ITP）和急性T淋巴细胞白血病（T-ALL）。
基因分析显示：（1）先证者同时携带VHL、ASXL3和CCR7基因种系突变以及获得性BCOR/NF1变异；（2）受ITP影响的后代仅遗传了ASXL3/CCR7突变；（3）T-ALL病例仅表现出VHL突变。先证者中的获得性突变（如BCOR/NF1）提示白血病发生的“双打击”模型。
本研究确定VHL是一个表现出异质性表型的家族性血液系统恶性肿瘤家系中的主要易感突变，其中ASXL3/CCR7变异可能作为表型修饰因子。这些发现支持在家族性血液系统疾病中采用基因型驱动的监测策略。
