PXD074216

PXD074216 is an original dataset announced via ProteomeXchange.

Title	Molecular principles of CRISPR-Cas13b design for selective silencing of oncogenic fusion transcripts
Description	Oncogenic gene fusions are key drivers of cancer, yet most remain untargetable by current therapies. Here, we establish CRISPR-PspCas13b as a personalisable platform for systematic silencing of various fusion transcripts. We reveal that recognition and cleavage of the breakpoint sequence by PspCas13b disrupts the fusion transcript, resulting in efficient protein depletion. Short and long-read RNA sequencing reveal that PspCas13b cleavage produces aberrant, translation-incompetent RNA isoforms with internal deletions proximal to the cleavage site. Importantly, we demonstrate that targeting the BCR::ABL1 breakpoint sequence efficiently degrades both canonical and drug-resistant BCR::ABL1 mutants, which are the primary drivers of tyrosine kinase inhibitor (TKI) resistance and relapse in chronic myeloid leukemia (CML). Molecular profiling revealed that PspCas13b impairs BCR::ABL1 tyrosine phosphokinase activity and triggers extensive transcriptomic and proteomic remodelling, ultimately leading to erythroid differentiation and apoptosis in CML cells that are fully resistant to clinical drugs. Beyond BCR::ABL1 mutants, personalised design of PspCas13b effectively silences other undruggable fusions, including RUNX1::RUNX1T1 and EWSR1::FLI1, key drivers in acute myeloid leukemia and in Ewing’s sarcoma, respectively. Collectively, this study establishes a molecular framework for precise and personalizable targeting of otherwise undruggable or drug-resistant oncogenic transcripts.
HostingRepository	PRIDE
AnnounceDate	2026-08-26
AnnouncementXML	Submission_2026-08-25_21:48:39.091.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Wenxin Hu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2026-02-08 23:07:25	ID requested
⏵ 1	2026-08-25 21:48:39	announced

Dataset with its publication pending

submitter keyword: cas13

Mohamed Fareh
contact affiliation	Peter MacCallum Cancer Centre, Melbourne, 3000, Australia
contact email	mohamed.fareh@petermac.org
lab head
Wenxin Hu
contact affiliation	1Peter MacCallum Cancer Centre, Melbourne, 3000, Australia 2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3052, Australia
contact email	wenxin.hu@petermac.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD074216
     1. Label: PRIDE project
     2. Name: Molecular principles of CRISPR-Cas13b design for selective silencing of oncogenic fusion transcripts