Grimm Juliane, Heckl Dirk, Klusmann Jan-Henning
Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Halle, Germany.
Front Oncol. 2021 Mar 11;11:636633. doi: 10.3389/fonc.2021.636633. eCollection 2021.
Individuals with Down syndrome are genetically predisposed to developing acute megakaryoblastic leukemia. This myeloid leukemia associated with Down syndrome (ML-DS) demonstrates a model of step-wise leukemogenesis with perturbed hematopoiesis already presenting , facilitating the acquisition of additional driver mutations such as truncating variants, which are pathognomonic to the disease. Consequently, the affected individuals suffer from a transient abnormal myelopoiesis (TAM)-a pre-leukemic state preceding the progression to ML-DS. In our review, we focus on the molecular mechanisms of the different steps of clonal evolution in Down syndrome leukemogenesis, and aim to provide a comprehensive view on the complex interplay between gene dosage imbalances, mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators.
唐氏综合征患者在基因上易患急性巨核细胞白血病。这种与唐氏综合征相关的髓系白血病（ML-DS）呈现出一种逐步白血病发生的模式，造血功能紊乱已经出现，这有利于获得额外的驱动突变，如截短变异，这些变异是该疾病的特征性表现。因此，受影响的个体患有短暂异常髓系造血（TAM）——一种在进展为ML-DS之前的白血病前期状态。在我们的综述中，我们关注唐氏综合征白血病发生过程中克隆进化不同步骤的分子机制，旨在全面了解基因剂量失衡、影响JAK-STAT信号通路、黏连蛋白复合物和表观遗传调节因子的突变与体细胞突变之间的复杂相互作用。
