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CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity
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 mech...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974466/ https://www.ncbi.nlm.nih.gov/pubmed/27460500 http://dx.doi.org/10.1038/ncomms12320 |
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author | Jacoby, Elad Nguyen, Sang M. Fountaine, Thomas J. Welp, Kathryn Gryder, Berkley Qin, Haiying Yang, Yinmeng Chien, Christopher D. Seif, Alix E. Lei, Haiyan Song, Young K. Khan, Javed Lee, Daniel W. Mackall, Crystal L. Gardner, Rebecca A. Jensen, Michael C. Shern, Jack F. Fry, Terry J. |
author_facet | Jacoby, Elad Nguyen, Sang M. Fountaine, Thomas J. Welp, Kathryn Gryder, Berkley Qin, Haiying Yang, Yinmeng Chien, Christopher D. Seif, Alix E. Lei, Haiyan Song, Young K. Khan, Javed Lee, Daniel W. Mackall, Crystal L. Gardner, Rebecca A. Jensen, Michael C. Shern, Jack F. Fry, Terry J. |
author_sort | Jacoby, Elad |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4974466 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49744662016-08-18 CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity Jacoby, Elad Nguyen, Sang M. Fountaine, Thomas J. Welp, Kathryn Gryder, Berkley Qin, Haiying Yang, Yinmeng Chien, Christopher D. Seif, Alix E. Lei, Haiyan Song, Young K. Khan, Javed Lee, Daniel W. Mackall, Crystal L. Gardner, Rebecca A. Jensen, Michael C. Shern, Jack F. Fry, Terry J. Nat Commun Article 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. Nature Publishing Group 2016-07-27 /pmc/articles/PMC4974466/ /pubmed/27460500 http://dx.doi.org/10.1038/ncomms12320 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Jacoby, Elad Nguyen, Sang M. Fountaine, Thomas J. Welp, Kathryn Gryder, Berkley Qin, Haiying Yang, Yinmeng Chien, Christopher D. Seif, Alix E. Lei, Haiyan Song, Young K. Khan, Javed Lee, Daniel W. Mackall, Crystal L. Gardner, Rebecca A. Jensen, Michael C. Shern, Jack F. Fry, Terry J. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity |
title | CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity |
title_full | CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity |
title_fullStr | CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity |
title_full_unstemmed | CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity |
title_short | CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity |
title_sort | cd19 car immune pressure induces b-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974466/ https://www.ncbi.nlm.nih.gov/pubmed/27460500 http://dx.doi.org/10.1038/ncomms12320 |
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