Kosmidou Aikaterini, Tragiannidis Athanasios, Gavriilaki Eleni
2nd Department of Internal Medicine, General Hospital of Kavala, 65500 Kavala, Greece.
2nd Department of Pediatrics, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece.
Cancers (Basel). 2023 Jun 21;15(13):3265. doi: 10.3390/cancers15133265.
Myeloid leukemia of Down syndrome (ML-DS) is characterized by a distinct natural history and is classified by the World Health Organization (WHO) as an independent entity, occurring with unique clinical and molecular features. The presence of a long preleukemic, myelodysplastic phase, called transient abnormal myelopoiesis (TAM), precedes the initiation of ML-DS and is defined by unusual chromosomal findings. Individuals with constitutional trisomy 21 have a profound dosage imbalance in the hematopoiesis-governing genes located on chromosome 21 and thus are subject to impaired fetal as well as to neonatal erythro-megakaryopoiesis. Almost all neonates with DS develop quantitative and morphological hematological abnormalities, yet still only 5-10% of them present with one of the preleukemic or leukemic conditions of DS. The acquired mutations in the key hematopoietic transcription factor gene , found solely in cells trisomic for chromosome 21, are considered to be the essential step for the selective growth advantage of leukemic cells. While the majority of cases of TAM remain clinically 'silent' or undergo spontaneous remission, the remaining 20% to 30% of them progress into ML-DS until the age of 4 years. The hypersensitivity of ML-DS blasts to chemotherapeutic agents, including but not limited to cytarabine, and drugs' increased infectious and cardiac toxicity have necessitated the development of risk-adapted treatment protocols for children with ML-DS. Recent advances in cytogenetics and specific molecular mechanisms involved in the evolution of TAM and ML-DS are reviewed here, as well as their integration in the improvement of risk stratification and targeted management of ML-DS.
唐氏综合征髓系白血病（ML-DS）具有独特的自然病程，世界卫生组织（WHO）将其归类为一个独立的实体，具有独特的临床和分子特征。在ML-DS发病之前，存在一个漫长的白血病前期骨髓增生异常阶段，称为短暂异常髓系造血（TAM），其特征是染色体异常。患有21号染色体三体综合征的个体，位于21号染色体上的造血调控基因存在严重的剂量失衡，因此胎儿及新生儿的红系和巨核系造血功能受损。几乎所有唐氏综合征新生儿都会出现血液学的数量和形态异常，但其中只有5%-10%会出现唐氏综合征的白血病前期或白血病状态。关键造血转录因子基因的获得性突变仅在21号染色体三体的细胞中发现，被认为是白血病细胞选择性生长优势的关键步骤。虽然大多数TAM病例在临床上“无症状”或自发缓解，但其余20%-30%会在4岁前发展为ML-DS。ML-DS原始细胞对化疗药物（包括但不限于阿糖胞苷）高度敏感，且药物的感染性和心脏毒性增加，因此有必要为ML-DS患儿制定风险适应性治疗方案。本文综述了细胞遗传学以及TAM和ML-DS演变过程中涉及的特定分子机制的最新进展，以及它们在改善ML-DS风险分层和靶向治疗中的整合。
