Internal Medicine, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.
Endocrinology Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.
Aging Clin Exp Res. 2021 Jul;33(7):1987-1992. doi: 10.1007/s40520-020-01709-7. Epub 2020 Sep 17.
Aging is associated with a higher risk of developing malignant diseases, including myelodysplastic syndromes, clonal disorders characterised by chronic cytopenias (anaemia, neutropenia and thrombocytopenia) and abnormal cellular maturation. Myelodysplastic syndromes arising in older subjects are influenced by combinations of acquired somatic genetic lesions driving evolution from clonal haematopoiesis to myelodysplastic syndromes and from myelodysplastic syndromes to acute leukaemia. A different pattern of mutations has been identified in a small subset of myelodysplastic syndromes arising in young patients with familial syndromes. In particular, dysregulation of ANKRD26, RUNX1 and ETV6 genes plays a role in familial thrombocytopenia with predisposition to myelodysplastic syndromes and acute leukaemia. Whether these genes affect thrombopoiesis in sporadic myelodysplastic syndrome with thrombocytopenia is still undefined. Thirty-one myelodysplastic syndromes subjects and 27 controls subjects were investigated. Genomic DNA was used for mutation screening (ETV6, RUNX1, 5'UTR ANKRD26 genes). Functional studies were performed in the MEG-01-akaryoblastic cell line. We found four novel variants of RUNX1 gene, all in elderly myelodysplastic syndromes subjects with thrombocytopenia. Functional studies of the variant p.Pro103Arg showed no changes in RUNX1 expression, but the variant was associated with deregulated high transcriptional activity of ANKRD26 in MEG-01 cells. RUNX1 variant p.Pro103Arg was also associated with increased viability and reduced apoptosis of MEG-01, as well as impaired platelet production. Our findings are consistent with dysregulation of ANKRD26 in RUNX1 haploinsufficiency. Lack of repression of ANKRD26 expression may contribute to thrombocytopenia of subjects with sporadic myelodysplastic syndromes.
衰老与恶性疾病风险增加相关，包括骨髓增生异常综合征、以慢性血细胞减少（贫血、中性粒细胞减少和血小板减少）和异常细胞成熟为特征的克隆性疾病。老年患者发生的骨髓增生异常综合征受获得性体细胞遗传病变组合的影响，这些病变可促使从克隆性造血向骨髓增生异常综合征演变，以及从骨髓增生异常综合征向急性白血病演变。在具有家族综合征的年轻患者中发生的一小部分骨髓增生异常综合征中，已确定存在不同的突变模式。特别是，ANKRD26、RUNX1 和 ETV6 基因的失调在易发生骨髓增生异常综合征和急性白血病的家族性血小板减少症中发挥作用。这些基因是否影响散发性骨髓增生异常综合征伴血小板减少症中的巨核细胞生成仍未确定。研究了 31 名骨髓增生异常综合征患者和 27 名对照患者。使用基因组 DNA 进行突变筛选（ETV6、RUNX1、5'UTR ANKRD26 基因）。在 MEG-01-巨核细胞系中进行功能研究。我们发现了 RUNX1 基因的四个新变体，均在老年骨髓增生异常综合征伴血小板减少症患者中发现。变体 p.Pro103Arg 的功能研究表明 RUNX1 表达没有变化，但该变体与 MEG-01 细胞中 ANKRD26 的转录活性失调有关。RUNX1 变体 p.Pro103Arg 还与 MEG-01 细胞活力增加和凋亡减少以及血小板生成受损相关。我们的发现与 RUNX1 杂合不足时 ANKRD26 失调一致。ANKRD26 表达缺乏抑制可能导致散发性骨髓增生异常综合征患者血小板减少。
