Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
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
_version_ 1782446549127659520
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
work_keys_str_mv AT jacobyelad cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT nguyensangm cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT fountainethomasj cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT welpkathryn cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT gryderberkley cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT qinhaiying cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT yangyinmeng cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT chienchristopherd cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT seifalixe cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT leihaiyan cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT songyoungk cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT khanjaved cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT leedanielw cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT mackallcrystall cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT gardnerrebeccaa cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT jensenmichaelc cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT shernjackf cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity
AT fryterryj cd19carimmunepressureinducesbprecursoracutelymphoblasticleukaemialineageswitchexposinginherentleukaemicplasticity