Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas.
Eur J Haematol. 2019 Feb;102(2):103-110. doi: 10.1111/ejh.13182. Epub 2018 Dec 18.
The application of next-generation sequencing (NGS) has enhanced our understanding of the genetic landscape in acquired aplastic anemia (AA). Parallel progress has been in addressing aspects underlying immune dysregulation in disease pathogenesis. Novel insights into the molecular and biologic mechanisms have led to a shift in the paradigm of AA, from a solely autoimmune pathogenic concept toward its recognition as a multifaceted pathophysiology characterized by cytogenetic abnormalities, recurrent somatic mutations, telomere attrition, and immune dysregulation. The detection of recurrent driver mutations disrupting myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)-associated genes has suggested a pathophysiologic link between clonal hematopoiesis in AA and the later development of these clonal disorders. Further, certain AA-related somatic genetic alterations may have clinical implications on treatment response, disease progression, and survival following immunosuppressive therapy. Going forward, wider validation of these genetic abnormalities will allow for their incorporation into a more informative risk stratification system that does not rely solely on clinical factors.
下一代测序（NGS）的应用增强了我们对获得性再生障碍性贫血（AA）遗传特征的理解。在解决疾病发病机制中免疫失调的各个方面也取得了平行进展。对分子和生物学机制的新认识导致 AA 范式的转变，从单纯的自身免疫发病概念转变为多方面的病理生理学，其特征是细胞遗传学异常、反复体细胞突变、端粒损耗和免疫失调。反复驱动突变的检测破坏了骨髓增生异常综合征（MDS）/急性髓系白血病（AML）相关基因，提示 AA 中的克隆性造血与这些克隆性疾病的后期发展之间存在病理生理学联系。此外，某些与 AA 相关的体细胞遗传改变可能对免疫抑制治疗后的治疗反应、疾病进展和生存有临床意义。展望未来，对这些遗传异常的更广泛验证将使其能够纳入更具信息量的风险分层系统，而不仅仅依赖于临床因素。
