Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.,Proceedings of the National Academy of Sciences of the United States of America

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Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2022-04-06 , DOI: 10.1073/pnas.2120787119
Yu-Ting Dai ₁ , Fan Zhang ₁ , Hai Fang ₁ , Jian-Feng Li _{1,

2} , Gang Lu ₁ , Lu Jiang ₁ , Bing Chen ₁ , Dong-Dong Mao ₁ , Yuan-Fang Liu ₁ , Jin Wang ₁ , Li-Jun Peng ₁ , Chong Feng _{1,

2} , Hai-Feng Chen ₃ , Jun-Xi Mu ₃ , Qun-Ling Zhang ₄ , Hao Wang ₅ , Hany Ariffin ₆ , Tan Ah Moy ₇ , Jing-Han Wang ₈ , Yin-Jun Lou ₈ , Su-Ning Chen _{9,

10} , Qian Wang ₉ , Hong Liu ₉ , Zhe Shan ₉ , Itaru Matsumura ₁₁ , Yasushi Miyazaki ₁₂ , Takahiko Yasuda ₁₃ , Li-Ping Dou ₅ , Xiao-Jing Yan ₁₄ , Jin-Song Yan ₁₅ , Allen Eng-Juh Yeoh _{16,

17,

18} , De-Pei Wu _{9,

10} , Hitoshi Kiyoi ₁₉ , Fumihiko Hayakawa ₂₀ , Jie Jin ₈ , Sheng-Yue Wang ₁ , Xiao-Jian Sun ₁ , Jian-Qing Mi ₁ , Zhu Chen ₁ , Jin-Yan Huang _{21,

22} , Sai-Juan Chen ₁

Affiliation

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240 Shanghai, China.
State Key Laboratory of Microbial metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Department of Bioinformatics and Biostatistics, National Experimental Teaching Center for Life Sciences and Biotechnology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240 Shanghai, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, 200032 Shanghai, China.
Department of Hematology, Chinese People's Liberation Army General Hospital, 100853 Beijing, China.
University of Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Department of Paediatrics, KK Women's & Children's Hospital, 229899 Singapore.
Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, 310058 Hangzhou, People's Republic of China.
National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, 215006 Suzhou, People's Republic of China.
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, 215006 Suzhou, People's Republic of China.
Division of Hematology and Rheumatology, Kindai University Faculty of Medicine, 5778502 Osaka, Japan.
Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, 8528521 Nagasaki, Japan.
Clinical Research Center, Nagoya Medical Center, National Hospital Organization, 4600001 Nagoya, Japan.
Department of Hematology, The First Affiliated Hospital of China Medical University, 110001 Liaoning, China.
Department of Hematology, Second Hospital of Dalian Medical University, 116027 Leaoning, People's Republic of China.
Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore.
Viva-University Children's Cancer Centre, Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, 119074 Singapore.
Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore.
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 4668550 Nagoya, Japan.
Department of Integrated Health Sciences, Division of Cellular and Genetic Sciences, Nagoya University Graduate School of Medicine, 4610047 Nagoya, Japan.
Center for Biomedical Big Data, The First Affiliated Hospital, School of Medicine, Zhejiang University, 310003 Hangzhou, China.
Cancer Center, Zhejiang University, 310058 Hangzhou, China.

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.

中文翻译：

在一项包含 707 例病例的国际研究中，对儿童和成人 T 细胞急性淋巴细胞白血病进行全转录组亚型分析。

T 细胞急性淋巴细胞白血病 (T-ALL) 是一种侵袭性 T 细胞祖细胞的恶性血液病，已知在儿科和成人患者中是一种异质性疾病。在这里，我们试图根据 707 名 T-ALL 患者（510 名儿科患者、190 名成人患者和 7 名年龄未知；599 名来自已发表的队列和 108 名新调查的患者）的转录组学情况，在分子水平上更好地了解该疾病。利用基因表达信息，我们能够识别 10 种亚型（G1-G10），包括以前未描述的以 GATA3 突变为特征的亚型，其中 GATA3R276Q 能够影响斑马鱼的淋巴细胞发育。通过与 T 细胞分化阶段的关联，我们发现 LYL1/LMO2/SPI1/HOXA (G1-G6) 的高表达可能代表早期 T 细胞祖细胞，前/皮质前/皮质期发病年龄相对较高，TLX3/TLX1高表达（G7-G8）的淋巴母细胞可在皮质/皮质后期被阻断，而NKX2-1/TAL1/高表达的淋巴母细胞LMO1 (G9-G10) 可能对应于 T 细胞发育的皮质/皮质后/成熟阶段。值得注意的是，成年患者在表观遗传调节因子以及参与 JAK-STAT 和 RAS 信号通路的基因之间存在更多协同突变，其中 44% 的 40 岁或以上 G1 患者携带 DNMT3A/IDH2 突变通常见于急性髓性白血病，这表明混合表型急性白血病的性质。而那些 NKX2-1/TAL1/LMO1 (G9-G10) 高表达的可能对应于 T 细胞发育的皮质/皮质后/成熟阶段。值得注意的是，成年患者在表观遗传调节因子以及参与 JAK-STAT 和 RAS 信号通路的基因之间存在更多协同突变，其中 44% 的 40 岁或以上 G1 患者携带 DNMT3A/IDH2 突变通常见于急性髓性白血病，这表明混合表型急性白血病的性质。而那些 NKX2-1/TAL1/LMO1 (G9-G10) 高表达的可能对应于 T 细胞发育的皮质/皮质后/成熟阶段。值得注意的是，成年患者在表观遗传调节因子以及参与 JAK-STAT 和 RAS 信号通路的基因之间存在更多协同突变，其中 44% 的 40 岁或以上 G1 患者携带 DNMT3A/IDH2 突变通常见于急性髓性白血病，这表明混合表型急性白血病的性质。

更新日期：2022-04-06

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