Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Cells. 2022 Nov 2;11(21):3475. doi: 10.3390/cells11213475.
Mutation of the gene is one of the major drivers of myelodysplastic neoplasias (MDS) and acute myeloid leukemia with myelodysplasia-related changes (AML-MR). mutations present in these hematopoietic malignancies form a distinct molecular genetic cluster with a worse prognosis than without the alteration. However, besides well-characterized hot-spot variants, a significant proportion of alterations are of uncertain clinical significance.
To enlighten so far unknown aspects, bone-marrow samples from altogether 77 patients are analyzed retrospectively with the diagnosis of AML-MR (26 cases), MDS-IB (12 cases), and MDS-LB (39 cases) according to WHO 2022 guidelines. Next-generation sequencing results are correlated with histological, cytogenetic, and survival data.
Twenty out of the 30 mutation types detected by NGS are not categorized in current public databases; thus, their clinical significance remained mysterious. Because of the interpretation difficulties and the absence of clinical correlations, pathogenicity is established based on in silico approaches. The 12 pathogenicity classification systems, as well as protein stability, protein-DNA, protein-protein interaction, and post-translational modification analyses are applied. We found statistically significant differences between AML/MDS groups considering p53 pathogenicity, protein structural changes, and overall survival. The largest number of abnormalities with the most severe consequences are found in AML-MR cases.
These molecular and in silico protein data further support that MDS with increased-blast (MDS-IB) is an intermediate group between AML-MR and MDS with low-blast (MDS-LB) patients, which frequently progresses to AML and is therefore considered a pre-leukemic condition.
基因的突变是骨髓增生异常性肿瘤（MDS）和伴骨髓增生异常相关改变的急性髓系白血病（AML-MR）的主要驱动因素之一。这些血液系统恶性肿瘤中的突变形成了一个独特的分子遗传学簇，与没有改变的相比预后更差。然而，除了特征明确的热点变异外，相当一部分的改变具有不确定的临床意义。
为了阐明迄今为止未知的方面，根据 2022 年 WHO 指南，我们对总共 77 例诊断为 AML-MR（26 例）、MDS-IB（12 例）和 MDS-LB（39 例）的患者的骨髓样本进行回顾性分析。将下一代测序结果与组织学、细胞遗传学和生存数据相关联。
通过 NGS 检测到的 30 种突变类型中的 20 种未被当前公共数据库分类；因此，其临床意义仍然神秘。由于解释困难且缺乏临床相关性，因此基于计算机方法来确定致病性。应用了 12 种致病性分类系统，以及蛋白质稳定性、蛋白质-DNA、蛋白质-蛋白质相互作用和翻译后修饰分析。考虑到 p53 的致病性、蛋白质结构变化和总生存，我们在 AML/MDS 组之间发现了统计学上的显著差异。在 AML-MR 病例中发现了数量最多且后果最严重的异常。
这些分子和计算机蛋白质数据进一步支持 MDS 伴高原始细胞增多（MDS-IB）是 AML-MR 和 MDS 伴低原始细胞增多（MDS-LB）患者之间的中间群体，它经常进展为 AML，因此被认为是一种白血病前状态。
