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

Autor:	Jacoby E; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Nguyen SM; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Fountaine TJ; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Welp K; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Gryder B; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Qin H; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Yang Y; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Chien CD; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Seif AE; Division of Oncology, The Children's Hospital of Philadelphia, and Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA., Lei H; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Song YK; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Khan J; Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Lee DW; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Mackall CL; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Gardner RA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Hospital, and Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA., Jensen MC; Ben Towne Center for Childhood Cancer Research, Seattle Children's Hospital, and Department of Pediatrics, University of Washington, Seattle, Washington 98105, USA., Shern JF; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA., Fry TJ; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2016 Jul 27; Vol. 7, pp. 12320. Date of Electronic Publication: 2016 Jul 27.
DOI:	10.1038/ncomms12320
Abstrakt:	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.
Databáze:	MEDLINE
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