Targeting senescent stemlike subpopulations in Philadelphia chromosome–like acute lymphoblastic leukemia
Abstract
Abstract Philadelphia chromosome–like B-cell acute lymphoblastic leukemia (Ph-like ALL) is driven by genetic alterations that induce constitutive kinase signaling and is associated with chemoresistance and high relapse risk in children and adults. Preclinical studies in the most common CRLF2-rearranged/JAK pathway-activated Ph-like ALL subtype have revealed variable responses to JAK inhibitor-based therapies, suggesting incomplete oncogene addiction and highlighting a need to elucidate alternative biologic dependencies and therapeutic vulnerabilities, whereas the ABL-class Ph-like ALL subtype seems preferentially sensitive to SRC/ABL- or PDGFRB-targeting inhibitors. Which patients may be responsive vs resistant to tyrosine kinase inhibitor (TKI)–based precision medicine approaches remains a critical knowledge gap. Using bulk and single-cell multiomics analyses, we profiled residual cells from CRLF2-rearranged or ABL1-rearranged Ph-like ALL patient–derived xenograft models treated in vivo with targeted inhibitors to identify TKI-resistant subpopulations and potential mechanisms of therapeutic escape. We detected a specific MYC dependency in Ph-like ALL cells and defined a new leukemia cell subpopulation with senescence-associated stem cell-like features regulated by AP-1 transcription factors. This dormant ALL subpopulation was effectively eradicated by dual pharmacologic inhibition of BCL-2 and JAK/STAT or SRC/ABL pathways, a clinically relevant therapeutic strategy. Single cell–derived molecular signatures of this senescence and stem/progenitor-like subpopulation further predicted poor clinical outcomes associated with other high-risk genetic subtypes of childhood B-ALL and thus may have broader prognostic applicability beyond Ph-like ALL.
Article Details
Authors (22)
Yang-yang Ding
8Departments of Oncology and Pediatrics, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
Jonathan H. Sussman
Kellyn Madden
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Joseph P. Loftus
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Robert K. Chen
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Catherine D. Falkenstein
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Diego A. Bárcenas López
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
David A. Hottman
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Benjamin Mathier
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA
Wenbao Yu
2Children's Hospital of Philadelphia, Philadelphia, United States
Jason Xu
Changya Chen
2Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
Chia-Hui Chen
5Children's Hospital of Philadelphia, Center for Childhood Cancer Research, Philadelphia, United States
Bing He
Shovik Bandyopadhyay
2Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Zhan Zhang
DongGeun Lee
2Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN
Hong Wang
Junmin Peng
Chi V. Dang
7Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
Kai Tan
Sarah K. Tasian