Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases
Yu-Ting Dai, Fan Zhang, Hai Fang, Jianfeng Li, Gang Lü, Lu Jiang, Bing Chen, Dongdong Mao, Yuanfang Liu, Jin Wang, Lijun Peng, Chong Feng, Haifeng Chen, Junxi Mu, Qunling Zhang, Hao Wang, Hany Ariffin, Tan Ah Moy, Jinghan Wang, Yinjun Lou, Suning Chen, Qian Wang, Hong Liu, Zhe Shan, Itaru Matsumura, Yasushi Miyazaki, Takahiko Yasuda, Liping Dou, Xiaojing Yan, Jinsong Yan, Allen Eng Juh Yeoh, Depei Wu, Hitoshi Kiyoi, Fumihiko Hayakawa, Jie Jin, Shengyue Wang, Xiao‐Jian Sun, Jian‐Qing Mi, Zhu Chen, Jin-Yan Huang, Sai‐Juan Chen
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 GATA3R276Q 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/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9–G10) might correspond to cortical/postcortical/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.