Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia

  • Cancer Cell. 2024 Apr 8;42(4):552-567.e6. doi: 10.1016/j.ccell.2024.03.003.
Xin Huang  1 ,  Yizhen Li  2 ,  Jingliao Zhang  3 ,  Lei Yan  4 ,  Huanbin Zhao  5 ,  Liang Ding  4 ,  Sheetal Bhatara  4 ,  Xu Yang  4 ,  Satoshi Yoshimura  5 ,  Wenjian Yang  5 ,  Seth E Karol  6 ,  Hiroto Inaba  6 ,  Charles Mullighan  7 ,  Mark Litzow  8 ,  Xiaofan Zhu  3 ,  Yingchi Zhang  3 ,  Wendy Stock  9 ,  Nitin Jain  10 ,  Elias Jabbour  10 ,  Steven M Kornblau  10 ,  Marina Konopleva  11 ,  Ching-Hon Pui  12 ,  Elisabeth Paietta  13 ,  William Evans  5 ,  Jiyang Yu  14 ,  Jun J Yang  15
Affiliations
  • 1. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui 230601, China.
  • 2. Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Hematology, Children's Hospital of Soochow University, Suzhou, Jiangsu 215003, China.
  • 3. Department of Pediatrics Blood Diseases Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
  • 4. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5. Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 6. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 7. Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 8. Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
  • 9. Department of Medicine Section of Hematology-Oncology, University of Chicago, Chicago, IL 60637, USA.
  • 10. Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 11. Department of Oncology and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 12. Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 13. Cancer Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 14. Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: [email protected].
  • 15. Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: [email protected].
PMID: 38593781 DOI: 10.1016/j.ccell.2024.03.003
Abstract

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.

Keywords
B cell development; L-asparaginase; NetBID2; acute lymphoblastic leukemia; developmental origins; hidden driver; single-cell multiome; single-cell systems pharmacology; venetoclax.
Products