Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases
Document Type
Article
Publication Date
4-1-2022
Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1-G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3(R276Q) capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1-G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7-G8) could be blocked at the cortical/post-cortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9-G10) might correspond to cortical/post-cortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.
Keywords
T-ALL, RNA sequencing, Molecular subtyping, Mutation, T cell differentiation stages
Divisions
fac_med
Funders
National Natural Science Foundation of China (NSFC) (81770205),National Natural Science Foundation of China (NSFC) (32170663),National Natural Science Foundation of China (NSFC) (81670147),National Natural Science Foundation of China (NSFC) (81861148030)
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
Volume
119
Issue
15
Publisher
Natl Acad Sciences India
Publisher Location
2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA