Xu Jason, Chen Changya, Sussman Jonathan H, Yoshimura Satoshi, Vincent Tiffaney, Pölönen Petri, Hu Jianzhong, Bandyopadhyay Shovik, Elghawy Omar, Yu Wenbao, Tumulty Joseph, Chen Chia-Hui, Li Elizabeth Y, Diorio Caroline, Shraim Rawan, Newman Haley, Uppuluri Lahari, Li Alexander, Chen Gregory M, Wu David W, Ding Yang-Yang, Xu Jessica A, Karanfilovski Damjan, Lim Tristan, Hsu Miles, Thadi Anusha, Ahn Kyung Jin, Wu Chi-Yun, Peng Jacqueline, Sun Yusha, Wang Alice, Mehta Rushabh, Frank David, Meyer Lauren, Loh Mignon L, Raetz Elizabeth A, Chen Zhiguo, Wood Brent L, Devidas Meenakshi, Dunsmore Kimberly P, Winter Stuart S, Chang Ti-Cheng, Wu Gang, Pounds Stanley B, Zhang Nancy R, Carroll William, Hunger Stephen P, Bernt Kathrin, Yang Jun J, Mullighan Charles G, Tan Kai, Teachey David T
Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Cancer. 2025 Jan;6(1):102-122. doi: 10.1038/s43018-024-00863-5. Epub 2024 Nov 25.
Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL.
对初始化疗的难治性和缓解后的复发是治愈T细胞急性淋巴细胞白血病（T-ALL）的主要障碍。虽然肿瘤异质性与治疗失败有关，但导致耐药和复发的细胞和遗传因素仍然未知。在这里，我们将肿瘤亚群与临床结果联系起来，创建了一份健康儿童造血图谱，并对40例不同的T-ALL病例进行了单细胞多组学分析。我们鉴定出一种与治疗失败和总体生存率低相关的骨髓祖细胞（BMP）样白血病亚群。BMP样母细胞的单细胞衍生分子特征预测了T-ALL多种亚型的不良预后，并揭示NOTCH1突变会累加地驱使T-ALL母细胞远离BMP样状态。通过计算机模拟和体外药物筛选，我们确定了BMP样母细胞对包括维奈克拉在内的凋亡诱导剂的治疗易感性。总体而言，我们的研究建立了多组学特征，用于对高危T-ALL进行快速风险分层和靶向治疗。
