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High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance.
- Source :
-
Nature communications [Nat Commun] 2022 Sep 22; Vol. 13 (1), pp. 5570. Date of Electronic Publication: 2022 Sep 22. - Publication Year :
- 2022
-
Abstract
- Following CART-19 immunotherapy for B-cell acute lymphoblastic leukaemia (B-ALL), many patients relapse due to loss of the cognate CD19 epitope. Since epitope loss can be caused by aberrant CD19 exon 2 processing, we herein investigate the regulatory code that controls CD19 splicing. We combine high-throughput mutagenesis with mathematical modelling to quantitatively disentangle the effects of all mutations in the region comprising CD19 exons 1-3. Thereupon, we identify ~200 single point mutations that alter CD19 splicing and thus could predispose B-ALL patients to developing CART-19 resistance. Furthermore, we report almost 100 previously unknown splice isoforms that emerge from cryptic splice sites and likely encode non-functional CD19 proteins. We further identify cis-regulatory elements and trans-acting RNA-binding proteins that control CD19 splicing (e.g., PTBP1 and SF3B4) and validate that loss of these factors leads to pervasive CD19 mis-splicing. Our dataset represents a comprehensive resource for identifying predictive biomarkers for CART-19 therapy.<br /> (© 2022. The Author(s).)
- Subjects :
- Alternative Splicing genetics
Antigens, CD19 genetics
Antigens, CD19 metabolism
Epitopes metabolism
Heterogeneous-Nuclear Ribonucleoproteins metabolism
Humans
Mutagenesis genetics
Mutation
Neoplasm Recurrence, Local genetics
Polypyrimidine Tract-Binding Protein genetics
Protein Isoforms genetics
RNA Splicing
RNA-Binding Proteins genetics
RNA-Binding Proteins metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
RNA Splice Sites
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 36138008
- Full Text :
- https://doi.org/10.1038/s41467-022-31818-y