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CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity

Author

Listed:
  • Elad Jacoby

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health
    Present address: Department of Pediatric Hematology and Oncology, The Edmond and Lily Safra’s Children’s Hospital, Sheba Medical Center, and Sackler School of Medicine, Tel Aviv University, Israel.)

  • Sang M. Nguyen

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Thomas J. Fountaine

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Kathryn Welp

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Berkley Gryder

    (Genetics Branch, National Cancer Institute, National Institutes of Health)

  • Haiying Qin

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Yinmeng Yang

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Christopher D. Chien

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Alix E. Seif

    (The Children’s Hospital of Philadelphia, Perelman School of Medicine of the University of Pennsylvania)

  • Haiyan Lei

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Young K. Song

    (Genetics Branch, National Cancer Institute, National Institutes of Health)

  • Javed Khan

    (Genetics Branch, National Cancer Institute, National Institutes of Health)

  • Daniel W. Lee

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Crystal L. Mackall

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Rebecca A. Gardner

    (Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, University of Washington)

  • Michael C. Jensen

    (Ben Towne Center for Childhood Cancer Research, Seattle Children’s Hospital, University of Washington)

  • Jack F. Shern

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Terry J. Fry

    (Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

Abstract

Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL.

Suggested Citation

  • Elad Jacoby & Sang M. Nguyen & Thomas J. Fountaine & Kathryn Welp & Berkley Gryder & Haiying Qin & Yinmeng Yang & Christopher D. Chien & Alix E. Seif & Haiyan Lei & Young K. Song & Javed Khan & Daniel, 2016. "CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12320
    DOI: 10.1038/ncomms12320
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    Cited by:

    1. Pablo Domizi & Jolanda Sarno & Astraea Jager & Milton Merchant & Kaithlen Zen B. Pacheco & Sean A. Yamada-Hunter & Maria Caterina Rotiroti & Yuxuan Liu & Reema Baskar & Warren D. Reynolds & Brian J. S, 2025. "IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    2. Duanhao Gong & Fangfei Xu & Wei Huang & Jianfeng Zhou & Lei Wang, 2022. "Difference in Leukemia Microenvironment Induced by PAX5 Mutations in Acute Lymphoblastic Leukemia," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 42(3), pages 33652-33660, March.
    3. Takashi Mikami & Itaru Kato & Akira Nishimura & Minenori Eguchi-Ishimae & Tatsuya Kamitori & Keiji Tasaka & Hirohito Kubota & Tomoya Isobe & Yoshinori Uchihara & Yui Namikawa & Satoru Hamada & Shinich, 2025. "Multi-omics analysis identifies an M-MDSC-like immunosuppressive phenotype in lineage-switched AML with KMT2A rearrangement," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    4. Marcus Deichmann & Giovanni Schiesaro & Keerthana Ramanathan & Katrine Zeeberg & Nanna M. T. Koefoed & Maria Ormhøj & Rasmus U. W. Friis & Ryan T. Gill & Sine R. Hadrup & Emil D. Jensen & Michael K. J, 2025. "A yeast surface display platform for characterizing CAR T cell responses to cancer antigens," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    5. Azucena Ramos & Catherine E. Koch & Yunpeng Liu-Lupo & Riley D. Hellinger & Taeyoon Kyung & Keene L. Abbott & Julia Fröse & Daniel Goulet & Khloe S. Gordon & Keith P. Eidell & Paul Leclerc & Charles A, 2023. "Leukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    6. Guillem Pascual-Pasto & Brendan McIntyre & Margaret G. Hines & Anna M. Giudice & Laura Garcia-Gerique & Jennifer Hoffmann & Pamela Mishra & Stephanie Matlaga & Simona Lombardi & Rawan Shraim & Patrick, 2024. "CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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