Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.
Yu-Ting DaiFan ZhangHai FangJian-Feng LiGang LuLu JiangBing ChenDong-Dong MaoYuan-Fang LiuJin WangLi-Jun PengChong FengHai-Feng ChenJun-Xi MuQun-Ling ZhangHao WangHany AriffinTan Ah MoyJing-Han WangYin-Jun LouSu-Ning ChenQian WangHong LiuZhe ShanItaru MatsumuraYasushi MiyazakiTakahiko YasudaLi-Ping DouXiao-Jing YanJin-Song YanAllen Eng-Juh YeohDe-Pei WuHitoshi KiyoiFumihiko HayakawaJie JinSheng-Yue WangXiao-Jian SunJian-Qing MiSaijuan ChenJin-Yan HuangSai-Juan ChenPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- acute lymphoblastic leukemia
- gene expression
- end stage renal disease
- poor prognosis
- chronic kidney disease
- newly diagnosed
- ejection fraction
- transcription factor
- peritoneal dialysis
- prognostic factors
- signaling pathway
- single cell
- systematic review
- randomized controlled trial
- allogeneic hematopoietic stem cell transplantation
- binding protein
- rna seq
- genome wide
- health information
- childhood cancer
- social media
- single molecule
- young adults
- patient reported outcomes
- epithelial mesenchymal transition
- high speed
- atomic force microscopy