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

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

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: jiyang.yu@stjude.org.
  • 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: jun.yang@stjude.org.
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.

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