Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases

• Main Authors: Dai, Yu-Ting, Zhang, Fan, Fang, Hai, Li, Jian-Feng, Lu, Gang, Jiang, Lu, Chen, Bing, Mao, Dong-Dong, Liu, Yuan-Fang, Wang, Jin, Peng, Li-Jun, Feng, Chong, Chen, Hai-Feng, Mu, Jun-Xi, Zhang, Qun-Ling, Wang, Hao, Ariffin, Hany, Moy, Tan Ah, Wang, Jing-Han, Lou, Yin-Jun, Chen, Su-Ning, Wang, Qian, Liu, Hong, Shan, Zhe, Matsumura, Itaru, Miyazaki, Yasushi, Yasuda, Takahiko, Dou, Li-Ping, Yan, Xiao-jing, Yan, Jin-Song, Yeoh, Allen Eng-Juh, Wu, De-Pei, Kiyoi, Hitoshi, Hayakawa, Fumihiko, Jin, Jie, Wang, Sheng-Yue, Sun, Xiao-Jian, Mi, Jian-Qing, Chen, Zhu, Huang, Jin-Yan, Chen, Sai-Juan
• Format: Article
• Published: Natl Acad Sciences India 2022
• Subjects: Q Science (General); R Medicine (General)
• Online Access: http://eprints.um.edu.my/42889/

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.