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  3. 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.
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.

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