CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity
Open Access
- 27 July 2016
- journal article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 7 (1), 12320
- https://doi.org/10.1038/ncomms12320
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.Keywords
This publication has 65 references indexed in Scilit:
- Lineage Switching in Acute Leukemias: A Consequence of Stem Cell Plasticity?Bone Marrow Research, 2012
- CD19 is a major B cell receptor–independent activator of MYC-driven B-lymphomagenesisJCI Insight, 2012
- Runx1 deletion or dominant inhibition reduces Cebpa transcription via conserved promoter and distal enhancer sites to favor monopoiesis over granulopoiesisBlood, 2012
- Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid LeukemiaNew England Journal of Medicine, 2011
- Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cellsBlood, 2011
- Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19Blood, 2010
- Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cellsBlood, 2010
- A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fateNature Immunology, 2010
- Long-term protection from syngeneic acute lymphoblastic leukemia by CpG ODN-mediated stimulation of innate and adaptive immune responsesBlood, 2009
- Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic LeukemiaScience, 2008