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Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells

Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not...

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Autores principales: van der Werf, Inge, Mondala, Phoebe K., Steel, S. Kathleen, Balaian, Larisa, Ladel, Luisa, Mason, Cayla N., Diep, Raymond H., Pham, Jessica, Cloos, Jacqueline, Kaspers, Gertjan J.L., Chan, Warren C., Mark, Adam, La Clair, James J., Wentworth, Peggy, Fisch, Kathleen M., Crews, Leslie A., Whisenant, Thomas C., Burkart, Michael D., Donohoe, Mary E., Jamieson, Catriona H.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040387/
https://www.ncbi.nlm.nih.gov/pubmed/36889320
http://dx.doi.org/10.1016/j.xcrm.2023.100962
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author van der Werf, Inge
Mondala, Phoebe K.
Steel, S. Kathleen
Balaian, Larisa
Ladel, Luisa
Mason, Cayla N.
Diep, Raymond H.
Pham, Jessica
Cloos, Jacqueline
Kaspers, Gertjan J.L.
Chan, Warren C.
Mark, Adam
La Clair, James J.
Wentworth, Peggy
Fisch, Kathleen M.
Crews, Leslie A.
Whisenant, Thomas C.
Burkart, Michael D.
Donohoe, Mary E.
Jamieson, Catriona H.M.
author_facet van der Werf, Inge
Mondala, Phoebe K.
Steel, S. Kathleen
Balaian, Larisa
Ladel, Luisa
Mason, Cayla N.
Diep, Raymond H.
Pham, Jessica
Cloos, Jacqueline
Kaspers, Gertjan J.L.
Chan, Warren C.
Mark, Adam
La Clair, James J.
Wentworth, Peggy
Fisch, Kathleen M.
Crews, Leslie A.
Whisenant, Thomas C.
Burkart, Michael D.
Donohoe, Mary E.
Jamieson, Catriona H.M.
author_sort van der Werf, Inge
collection PubMed
description Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not been extensively studied in pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses of FACS-purified hematopoietic stem and progenitor cells followed by differential splicing analyses, dual-fluorescence lentiviral splicing reporter assays, and the potential of a selective splicing modulator, Rebecsinib, in pAML. Using these methods, we discover transcriptomic splicing deregulation typified by differential exon usage. In addition, we discover downregulation of splicing regulator RBFOX2 and CD47 splice isoform upregulation. Importantly, splicing deregulation in pAML induces a therapeutic vulnerability to Rebecsinib in survival, self-renewal, and lentiviral splicing reporter assays. Taken together, the detection and targeting of splicing deregulation represent a potentially clinically tractable strategy for pAML therapy.
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spelling pubmed-100403872023-03-28 Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells van der Werf, Inge Mondala, Phoebe K. Steel, S. Kathleen Balaian, Larisa Ladel, Luisa Mason, Cayla N. Diep, Raymond H. Pham, Jessica Cloos, Jacqueline Kaspers, Gertjan J.L. Chan, Warren C. Mark, Adam La Clair, James J. Wentworth, Peggy Fisch, Kathleen M. Crews, Leslie A. Whisenant, Thomas C. Burkart, Michael D. Donohoe, Mary E. Jamieson, Catriona H.M. Cell Rep Med Article Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not been extensively studied in pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses of FACS-purified hematopoietic stem and progenitor cells followed by differential splicing analyses, dual-fluorescence lentiviral splicing reporter assays, and the potential of a selective splicing modulator, Rebecsinib, in pAML. Using these methods, we discover transcriptomic splicing deregulation typified by differential exon usage. In addition, we discover downregulation of splicing regulator RBFOX2 and CD47 splice isoform upregulation. Importantly, splicing deregulation in pAML induces a therapeutic vulnerability to Rebecsinib in survival, self-renewal, and lentiviral splicing reporter assays. Taken together, the detection and targeting of splicing deregulation represent a potentially clinically tractable strategy for pAML therapy. Elsevier 2023-03-07 /pmc/articles/PMC10040387/ /pubmed/36889320 http://dx.doi.org/10.1016/j.xcrm.2023.100962 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
van der Werf, Inge
Mondala, Phoebe K.
Steel, S. Kathleen
Balaian, Larisa
Ladel, Luisa
Mason, Cayla N.
Diep, Raymond H.
Pham, Jessica
Cloos, Jacqueline
Kaspers, Gertjan J.L.
Chan, Warren C.
Mark, Adam
La Clair, James J.
Wentworth, Peggy
Fisch, Kathleen M.
Crews, Leslie A.
Whisenant, Thomas C.
Burkart, Michael D.
Donohoe, Mary E.
Jamieson, Catriona H.M.
Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
title Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
title_full Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
title_fullStr Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
title_full_unstemmed Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
title_short Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
title_sort detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10040387/
https://www.ncbi.nlm.nih.gov/pubmed/36889320
http://dx.doi.org/10.1016/j.xcrm.2023.100962
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