Trisomy 21是唐氏综合症的遗传原因，是最常见的先天性染色体异常。在儿童期，它与急性淋巴细胞白血病（ALL）的风险增加20倍，导致独特的白血病生物学。为了全面定义DS-ALL的基因组景观，我们对295个案例进行了全基因组测序和整个转录组测序（RNA-Seq）。我们的综合基因组分析鉴定了15个DS-ALL分子亚型，与2257个非DS-ALL案例相比，CRLF2-r，IGH :: IGF2BP1和C / EBP修改（C / EBPalt）亚型显著富集。我们观察到CEBPD，CEBPA和CEBPE基因的异常激活在10.5％的DS-ALL案例中存在，通过各种基因组机制，包括染色体重排和导致增强子劫持的非编码突变。42.3％的C / EBP激活型DS-ALL还具有FLT3点突变或插入/缺失相伴，而其他亚型仅占4.1％（P = 7.2×10 -6）。CEBPD的过表达增强了小鼠造血祖细胞向前B细胞的分化，特别是在DS遗传背景下。值得注意的是，RAG介导的体细胞基因组异常在DS-ALL中很常见，占结构性改变的中位数的27.5％，而在非DS-ALL中仅占7.7％（P = 2.1×10-12）。 CRLF2重组DS-ALL的非监督分层聚类分析发现该组内存在显著的异质性，其中BCR :: ABL1-like子集与较差的事件无病生存相关（危险比= 5.27，P = 9.3×10-8），即使在调整已知临床危险因素后（危险比= 4.32; P = 0.0020）。这些结果提供了对DS-ALL生物学的重要见解，并指向针对性治疗和治疗个性化的机会。版权所有©2023年美国血液学会。

Trisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases. Our integrated genomic analyses identified 15 molecular subtypes of DS-ALL, with marked enrichment of CRLF2-r, IGH::IGF2BP1, and C/EBP altered (C/EBPalt) subtypes compared to 2257 non-DS-ALL cases. We observed abnormal activation of the CEBPD, CEBPA, and CEBPE genes in 10.5% of DS-ALL cases, via a variety of genomic mechanisms, including chromosomal rearrangements and noncoding mutations leading to enhancer hijacking. 42.3% of C/EBP-activated DS-ALL also have concomitant FLT3 point mutation or indel, relative to 4.1% in other subtypes (P=7.2×10-6). CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, RAG-mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared to 7.7% in non-DS-ALL (P=2.1×10-12). Unsupervised hierarchical clustering analyses of CRLF2-rearranged DS-ALL identified substantial heterogeneity within this group, with the BCR::ABL1-like subset linked to an inferior event-free survival (hazard ratio=5.27, P=9.3×10-8), even after adjusting for known clinical risk factors (hazard ratio=4.32; P=0.0020). These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.Copyright © 2023 American Society of Hematology.