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Alternative splicing of its 5′-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies

Overview of attention for article published in Blood, September 2023
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About this Attention Score

  • In the top 5% of all research outputs scored by Altmetric
  • Among the highest-scoring outputs from this source (#21 of 33,393)
  • High Attention Score compared to outputs of the same age (99th percentile)
  • High Attention Score compared to outputs of the same age and source (99th percentile)

Mentioned by

news
67 news outlets
twitter
31 X users
wikipedia
1 Wikipedia page

Citations

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10 Dimensions

Readers on

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24 Mendeley
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Title
Alternative splicing of its 5′-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies
Published in
Blood, September 2023
DOI 10.1182/blood.2023020400
Pubmed ID
Authors

Zhiwei Ang, Luca Paruzzo, Katharina E. Hayer, Carolin Schmidt, Manuel Torres Diz, Feng Xu, Urvi Zankharia, Yunlin Zhang, Samantha Soldan, Sisi Zheng, Catherine D. Falkenstein, Joseph P. Loftus, Scarlett Y. Yang, Mukta Asnani, Patricia King Sainos, Vinodh Pillai, Emeline Chong, Marilyn M. Li, Sarah K. Tasian, Yoseph Barash, Paul M. Lieberman, Marco Ruella, Stephen J. Schuster, Andrei Thomas-Tikhonenko

Abstract

Aberrant skipping of coding exons in CD19 and CD22 compromises responses to immunotherapy for B-cell malignancies. Here, we show that the MS4A1 gene encoding human CD20 also produces several mRNA isoforms with distinct 5' untranslated regions (5'-UTR). Four variants (V1-4) were detectable by RNA-seq in distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant by far. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform was found to contain upstream open reading frames (uORFs) and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching Morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, while V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed CAR T cells were able to kill both V3- and V1-expressing cells, but the bispecific T cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on four post-mosunetuzumab follicular lymphoma relapses and discovered that in two of them downregulation of CD20 was accompanied by the V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.

X Demographics

X Demographics

The data shown below were collected from the profiles of 31 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 24 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 24 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 6 25%
Unspecified 2 8%
Student > Ph. D. Student 2 8%
Student > Bachelor 1 4%
Student > Doctoral Student 1 4%
Other 1 4%
Unknown 11 46%
Readers by discipline Count As %
Medicine and Dentistry 4 17%
Biochemistry, Genetics and Molecular Biology 3 13%
Unspecified 2 8%
Immunology and Microbiology 2 8%
Agricultural and Biological Sciences 1 4%
Other 0 0%
Unknown 12 50%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 512. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 24 November 2023.
All research outputs
#50,191
of 25,537,395 outputs
Outputs from Blood
#21
of 33,393 outputs
Outputs of similar age
#1,075
of 353,173 outputs
Outputs of similar age from Blood
#2
of 159 outputs
Altmetric has tracked 25,537,395 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 99th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 33,393 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 7.6. This one has done particularly well, scoring higher than 99% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 353,173 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 99% of its contemporaries.
We're also able to compare this research output to 159 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 99% of its contemporaries.