Chen Changya, Xu Jason, Sussman Jonathan H, Vincent Tiffaney, Tumulty Joseph S, Yoshimura Satoshi, Alikarami Fatemeh, Yu Wenbao, Ding Yang-Yang, Chen Chia-Hui, Li Elizabeth Y, Yang Austin, Qin Xiaohuan, Bandyopadhyay Shovik, Peng Jacqueline, Pölönen Petri, Newman Haley, Wood Brent L, Hu Jianzhong, Shraim Rawan, Hughes Andrew D, Diorio Caroline, Uppuluri Lahari, Shi Gongping, Ryan Theresa, Fuller Tori, Loh Mignon L, Raetz Elizabeth A, Hunger Stephen P, Pounds Stanley B, Mullighan Charles G, Frank David, Yang Jun J, Bernt Kathrin M, Teachey David T, Tan Kai
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Tianjin Institutes of Health Science, Tianjin, China.
Blood. 2025 Jun 5;145(23):2685-2700. doi: 10.1182/blood.2024027270.
The critical role of leukemia-initiating cells as a therapy-resistant population in myeloid leukemia is well established. However, the molecular signatures of such cells in acute lymphoblastic leukemia remain underexplored. Moreover, their role in therapy response and patient prognosis is yet to be systematically investigated across various types of acute leukemia. We used single-cell multiomics to analyze diagnostic specimens from 96 pediatric patients with acute lymphoblastic, myeloid, and lineage-ambiguous leukemias. Through the integration of single-cell multiomics with extensive bulk RNA sequencing and clinical data sets, we uncovered a prevalent, chemotherapy-resistant subpopulation that resembles hematopoietic stem and progenitor cells (HSPC-like) and is associated with poor clinical outcomes across all subtypes investigated. We identified a core transcriptional regulatory network (TRN) in HSPC-like blasts that is combinatorially controlled by HOXA/AP1/CEBPA. This TRN signature can predict chemotherapy response and long-term clinical outcomes. We identified shared potential therapeutic targets against HSPC-like blasts, including FLT3, BCL2, and the PI3K pathway. Our study provides a framework for linking intratumoral heterogeneity with therapy response, patient outcomes, and the discovery of new therapeutic targets for pediatric acute leukemias.
白血病起始细胞作为髓系白血病中耐药细胞群的关键作用已得到充分证实。然而，急性淋巴细胞白血病中这类细胞的分子特征仍未得到充分研究。此外，它们在治疗反应和患者预后中的作用尚未在各类急性白血病中进行系统研究。我们使用单细胞多组学技术分析了96例患有急性淋巴细胞白血病、髓系白血病和谱系不明确白血病的儿科患者的诊断标本。通过将单细胞多组学与广泛的大量RNA测序和临床数据集相结合，我们发现了一个普遍存在的、对化疗耐药的亚群，该亚群类似于造血干细胞和祖细胞（HSPC样），并且与所有研究亚型的不良临床结果相关。我们在HSPC样母细胞中鉴定了一个核心转录调控网络（TRN），该网络由HOXA/AP1/CEBPA组合控制。这个TRN特征可以预测化疗反应和长期临床结果。我们确定了针对HSPC样母细胞的共同潜在治疗靶点，包括FLT3、BCL2和PI3K通路。我们的研究为将肿瘤内异质性与治疗反应、患者预后以及发现儿科急性白血病的新治疗靶点联系起来提供了一个框架。
