Genomic Landscape of Down Syndrome-Associated Acute Lymphoblastic Leukemia

Authors

Zhenhua Li
Ti-Cheng Chang
Jacob J Junco
Meenakshi Devidas
Yizhen Li
Wenjian Yang
Xin Huang
Dale J Hedges
Zhongshan Cheng
Mary Shago
Andrew J Carroll
Nyla A Heerema
Julie Gastier-Foster
Brent L Wood
Michael J Borowitz
Lauren Sanclemente
Elizabeth A Raetz
Stephen P Hunger
Eleanor Feingold
Tracie C Rosser
Stephanie L Sherman
Mignon L Loh
Charles G Mullighan
Jiyang Yu
Gang Wu
Philip J Lupo
Karen R Rabin
Jun J Yang

Language

English

Publication Date

7-13-2023

Journal

Blood

DOI

10.1182/blood.2023019765

PMID

37001051

PMCID

PMC10352600

PubMedCentral® Posted Date

4-5-2023

PubMedCentral® Full Text Version

Post-print

Abstract

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 with 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. A total of 42.3% of C/EBP-activated DS-ALL also have concomitant FLT3 point mutations or insertions/deletions, compared with 4.1% in other subtypes. CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, recombination-activating gene-mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared with 7.7% in non-DS-ALL. 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, even after adjusting for known clinical risk factors. These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.

Keywords

Animals, Mice, Down Syndrome, Mutation, Risk Factors, Genomics, Chromosome Aberrations, Precursor Cell Lymphoblastic Leukemia-Lymphoma

Published Open-Access

yes

Recommended Citation

Li, Zhenhua; Chang, Ti-Cheng; Junco, Jacob J; et al., "Genomic Landscape of Down Syndrome-Associated Acute Lymphoblastic Leukemia" (2023). Faculty and Staff Publications. 2366.
https://digitalcommons.library.tmc.edu/baylor_docs/2366