A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia
Jason Xu, Changya Chen, Jonathan Sussman, Satoshi Yoshimura, Tiffaney L. Vincent, Petri Pölönen, Jianzhong Hu, Shovik Bandyopadhyay, Omar Elghawy, Wenbao Yu, Joseph S. Tumulty, Chia-Hui Chen, Elizabeth Y. Li, Caroline Diorio, Rawan Shraim, Haley Newman, Lahari Uppuluri, Alexander Li, Gregory M. Chen, David W. Wu, Yangyang Ding, Jessica Xu, Damjan Karanfilovski, Tristan Lim, Miles Hsu, Anusha Thadi, Kyung Jin Ahn, Chi-Yun Wu, Jacqueline Peng, Yusha Sun, Alice Wang, Rushabh Mehta, David B. Frank, Lauren K. Meyer, Mignon L. Loh, Elizabeth A. Raetz, Zhiguo Chen, Brent L. Wood, Meenakshi Devidas, Kimberly P. Dunsmore, Stuart S. Winter, Ti‐Cheng Chang, Gang Wu, Stanley Pounds, Nancy R. Zhang, William L. Carroll, Stephen P. Hunger, Kathrin M. Bernt, Jun J. Yang, Charles G. Mullighan, Kai Tan, David T. Teachey
Abstract
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.