High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance

Mariela Cortés-López, Laura Schulz, Mihaela Enculescu, Claudia Paret, Bea Spiekermann, Mathieu Quesnel-Vallières, Manuel Torres-Diz, Sebastian Unic, Anke Busch, Anna Orekhova, Monika Kuban, Mikhail Mesitov, Miriam M. Mulorz, Rawan Shraim, Fridolin Kielisch, Jörg Faber, Yoseph Barash, Andrei Thomas-Tikhonenko, Kathi Zarnack (), Stefan Legewie () and Julian König ()
Additional contact information
Mariela Cortés-López: Institute of Molecular Biology (IMB)
Laura Schulz: Institute of Molecular Biology (IMB)
Mihaela Enculescu: Institute of Molecular Biology (IMB)
Claudia Paret: University Medical Center of the Johannes Gutenberg University Mainz
Bea Spiekermann: Institute of Molecular Biology (IMB)
Mathieu Quesnel-Vallières: Perelman School of Medicine at the University of Pennsylvania
Manuel Torres-Diz: Children’s Hospital of Philadelphia
Sebastian Unic: University of Stuttgart
Anke Busch: Institute of Molecular Biology (IMB)
Anna Orekhova: Institute of Molecular Biology (IMB)
Monika Kuban: University of Stuttgart
Mikhail Mesitov: Institute of Molecular Biology (IMB)
Miriam M. Mulorz: Institute of Molecular Biology (IMB)
Rawan Shraim: Children’s Hospital of Philadelphia
Fridolin Kielisch: Institute of Molecular Biology (IMB)
Jörg Faber: University Medical Center of the Johannes Gutenberg University Mainz
Yoseph Barash: Perelman School of Medicine at the University of Pennsylvania
Andrei Thomas-Tikhonenko: Children’s Hospital of Philadelphia
Kathi Zarnack: Buchmann Institute for Molecular Life Sciences (BMLS)
Stefan Legewie: Institute of Molecular Biology (IMB)
Julian König: Institute of Molecular Biology (IMB)

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31818-y

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