Single-cell panleukemia signatures of HSPC-like blasts predict drug response and clinical outcome
Abstract
Abstract 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.
Article Details
Authors (36)
Changya Chen
2Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Jason Xu
Jonathan H. Sussman
Tiffaney Vincent
3Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
Joseph S. Tumulty
3Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Satoshi Yoshimura
Department of Pharmacy and Pharmaceutical Sciences
Fatemeh Alikarami
1Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Oncology, Philadelphia, United States
Wenbao Yu
2Children's Hospital of Philadelphia, Philadelphia, United States
Yang-yang Ding
8Departments of Oncology and Pediatrics, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
Chia-Hui Chen
5Children's Hospital of Philadelphia, Center for Childhood Cancer Research, Philadelphia, United States
Elizabeth Y. Li
3Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA
Austin Yang
7Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA
Xiaohuan Qin
Shovik Bandyopadhyay
2Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Jacqueline Peng
4Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Petri Pölönen
Haley Newman
1Children's Hospital of Philadelphia, Division of Oncology, Philadelphia, United States
Brent L. Wood
Department of Pathology and Laboratory Medicine, Children’s Hospital of Los Angeles, Los Angeles
Jianzhong Hu
Rawan Shraim
Andrew D. Hughes
3Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Caroline Diorio
Lahari Uppuluri
4Children's Hospital of Philadelphia, Division of Oncology and Center for Childhood Cancer Research, Philadelphia, United States
Gongping Shi
3Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Theresa Ryan
3Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Tori Fuller
3Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Mignon L. Loh
Seattle Children’s Hospital, Seattle
Elizabeth A. Raetz
Department of Pediatrics and Perlmutter Cancer Center, NYU Langone Health, New York
Stephen P. Hunger
Department of Pediatrics and the Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia
Stanley B. Pounds
3Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN
Charles G. Mullighan
David Frank
Jun J. Yang
Department of Pharmacy and Pharmaceutical Sciences
Kathrin M. Bernt
David T. Teachey
Kai Tan