| Autor: |
Stefan Legewie, Kathi Zarnack, Claudia Paret, Mariela Cortés-López, Jörg Faber, Fridolin Kielisch, Mathieu Quesnel-Vallières, Anna Orekhova, Andrei Thomas-Tikhonenko, Anke Busch, Mihaela Enculescu, Julian König, Laura Schulz, Bea Spiekermann, Manuel Torres-Diz, Yoseph Barash |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
During 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 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 enhanced CD19 mis-splicing. Our dataset represents a comprehensive resource for potential prognostic factors predicting success of CART-19 therapy.HighlightsMutations in relapsed CART-19 patients lead to CD19 mis-splicingHigh-throughput mutagenesis uncovers ~200 single point mutations with a potential role in CART-19 therapy resistanceMany mutations generate non-functional CD19 proteins by activating cryptic splice sitesRNA-binding proteins such as PTBP1 are key to the expression of properly spliced, CART-19 immunotherapy-sensitive isoforms |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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