Cargando…

FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells

Noncanonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow (BM) and tonsil donors, performed RNA sequencing, and examined transcript...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Scarlett Y., Hayer, Katharina E., Fazelinia, Hossein, Spruce, Lynn A., Asnani, Mukta, Black, Kathryn L., Naqvi, Ammar S., Pillai, Vinodh, Barash, Yoseph, Elenitoba-Johnson, Kojo S. J., Thomas-Tikhonenko, Andrei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10111352/
https://www.ncbi.nlm.nih.gov/pubmed/36322817
http://dx.doi.org/10.1182/bloodadvances.2022007910
_version_ 1785027434538598400
author Yang, Scarlett Y.
Hayer, Katharina E.
Fazelinia, Hossein
Spruce, Lynn A.
Asnani, Mukta
Black, Kathryn L.
Naqvi, Ammar S.
Pillai, Vinodh
Barash, Yoseph
Elenitoba-Johnson, Kojo S. J.
Thomas-Tikhonenko, Andrei
author_facet Yang, Scarlett Y.
Hayer, Katharina E.
Fazelinia, Hossein
Spruce, Lynn A.
Asnani, Mukta
Black, Kathryn L.
Naqvi, Ammar S.
Pillai, Vinodh
Barash, Yoseph
Elenitoba-Johnson, Kojo S. J.
Thomas-Tikhonenko, Andrei
author_sort Yang, Scarlett Y.
collection PubMed
description Noncanonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow (BM) and tonsil donors, performed RNA sequencing, and examined transcript variants. We identified 150 genes that harbor local splicing variations in all pairwise comparisons. One of them encodes FBXW7, an E3 ubiquitin ligase implicated as a driver in several blood cancers. Surprisingly, we discovered that in normal human pro-B cells, the predominant transcript used an alternative first exon to produce the poorly characterized FBXW7β isoform, previously thought to be restricted to neural tissues. The FBXW7β transcript was also abundant in cell lines and primary samples of pediatric B-cell acute lymphoblastic leukemia (B-ALL), which originates in the BM. When overexpressed in a heterologous cell system, this transcript yielded the expected protein product, as judged by anti-FLAG immunoblotting and mass spectrometry. Furthermore, in REH B-ALL cells, FBXW7β mRNA was the only FBXW7 isoform enriched in the polyribosome fraction. To shed light on possible functions of FBXW7β, we used gain- and loss-of-function approaches and identified an FBXW7-dependent inflammatory gene signature, apparent in a subset of B-ALL with high FBXW7β expression. This signature contained several members of the tumor necrosis factor superfamily, including those comprising the HLA Class III cluster (LTB, LST1, NCR3, LTA, and NFKBIL1). Our findings suggest that FBXW7β expression drives proinflammatory responses, which could contribute to normal B-cell development, leukemogenesis, and responses to anticancer therapies.
format Online
Article
Text
id pubmed-10111352
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher The American Society of Hematology
record_format MEDLINE/PubMed
spelling pubmed-101113522023-04-19 FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells Yang, Scarlett Y. Hayer, Katharina E. Fazelinia, Hossein Spruce, Lynn A. Asnani, Mukta Black, Kathryn L. Naqvi, Ammar S. Pillai, Vinodh Barash, Yoseph Elenitoba-Johnson, Kojo S. J. Thomas-Tikhonenko, Andrei Blood Adv Lymphoid Neoplasia Noncanonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow (BM) and tonsil donors, performed RNA sequencing, and examined transcript variants. We identified 150 genes that harbor local splicing variations in all pairwise comparisons. One of them encodes FBXW7, an E3 ubiquitin ligase implicated as a driver in several blood cancers. Surprisingly, we discovered that in normal human pro-B cells, the predominant transcript used an alternative first exon to produce the poorly characterized FBXW7β isoform, previously thought to be restricted to neural tissues. The FBXW7β transcript was also abundant in cell lines and primary samples of pediatric B-cell acute lymphoblastic leukemia (B-ALL), which originates in the BM. When overexpressed in a heterologous cell system, this transcript yielded the expected protein product, as judged by anti-FLAG immunoblotting and mass spectrometry. Furthermore, in REH B-ALL cells, FBXW7β mRNA was the only FBXW7 isoform enriched in the polyribosome fraction. To shed light on possible functions of FBXW7β, we used gain- and loss-of-function approaches and identified an FBXW7-dependent inflammatory gene signature, apparent in a subset of B-ALL with high FBXW7β expression. This signature contained several members of the tumor necrosis factor superfamily, including those comprising the HLA Class III cluster (LTB, LST1, NCR3, LTA, and NFKBIL1). Our findings suggest that FBXW7β expression drives proinflammatory responses, which could contribute to normal B-cell development, leukemogenesis, and responses to anticancer therapies. The American Society of Hematology 2022-11-05 /pmc/articles/PMC10111352/ /pubmed/36322817 http://dx.doi.org/10.1182/bloodadvances.2022007910 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. 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 Lymphoid Neoplasia
Yang, Scarlett Y.
Hayer, Katharina E.
Fazelinia, Hossein
Spruce, Lynn A.
Asnani, Mukta
Black, Kathryn L.
Naqvi, Ammar S.
Pillai, Vinodh
Barash, Yoseph
Elenitoba-Johnson, Kojo S. J.
Thomas-Tikhonenko, Andrei
FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells
title FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells
title_full FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells
title_fullStr FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells
title_full_unstemmed FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells
title_short FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells
title_sort fbxw7β isoform drives transcriptional activation of the proinflammatory tnf cluster in human pro-b cells
topic Lymphoid Neoplasia
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10111352/
https://www.ncbi.nlm.nih.gov/pubmed/36322817
http://dx.doi.org/10.1182/bloodadvances.2022007910
work_keys_str_mv AT yangscarletty fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT hayerkatharinae fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT fazeliniahossein fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT sprucelynna fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT asnanimukta fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT blackkathrynl fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT naqviammars fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT pillaivinodh fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT barashyoseph fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT elenitobajohnsonkojosj fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells
AT thomastikhonenkoandrei fbxw7bisoformdrivestranscriptionalactivationoftheproinflammatorytnfclusterinhumanprobcells