Open AccessCD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity
Author(s) -
Elad Jacoby,
Sang Nguyen,
Thomas J. Fountaine,
Kathryn M Welp,
Berkley E. Gryder,
Haiying Qin,
Yinmeng Yang,
Christopher Chien,
Alix E. Seif,
Haiyan Lei,
Young Song,
Javed Khan,
Daniel W. Lee,
Crystal L. Mackall,
Rebecca Gardner,
Michael C. Jensen,
Jack F. Shern,
Terry J. Fry
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms12320
Subject(s) - cd19 , lineage (genetic) , chimeric antigen receptor , biology , progenitor cell , haematopoiesis , cancer research , reprogramming , myeloid , b cell , immunology , antigen , microbiology and biotechnology , immunotherapy , immune system , stem cell , cell , genetics , antibody , gene
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.