PXD051178

PXD051178 is an original dataset announced via ProteomeXchange.

Title	Locking CBL in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukaemia (part 1)
Description	Casitas B-lineage lymphoma (CBL) is critical to the negative regulation of receptor protein tyrosine kinases (RTKs). Mutant CBL can act as an adaptor and gain function to cause myeloproliferative diseases. Currently, there is no beneficial treatment available for leukaemia patients with CBL mutations. Using phage-display technique, we identified a peptide inhibitor CBLock that binds a pocket in CBL’s tyrosine kinase binding domain (TKBD) in its native conformation as revealed by a crystal structure. CBLock inhibits proliferation, causes cell cycle arrest and apoptosis in leukaemia cells that harbour CBL mutations. CBLock disrupts the interaction between CBL mutants and RTK/adaptor protein, hindering the gain-of-function of CBL mutants. We find reduced tumour progression and improved survival upon conditional expression of CBLock in a xenograft AML model. CBLock also resulted in reduced FLT3 downstream signalling. Therefore, inhibiting CBL-TKBD in its native state presents a useful therapeutic opportunity in targeting mutant/inactive CBL-dependent leukaemia.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_02:41:31.474.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sergio Lilla
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-04-03 07:50:11	ID requested
⏵ 1	2025-05-06 02:41:31	announced

10.1016/J.YMTHE.2025.04.042;

submitter keyword: peptide inhibitor CBLock, CBL’s tyrosine kinase binding domain, leukaemia,Casitas B-lineage lymphoma (CBL)

Sara Rossana Zanivan
contact affiliation	CRUK - Scotland Institute - Switchback Rd, Bearsden, Glasgow G61 1BD - United Kingdom
contact email	Sara.Zanivan@glasgow.ac.uk
lab head
Sergio Lilla
contact affiliation	Proteomics
contact email	s.lilla@beatson.gla.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD051178
     1. Label: PRIDE project
     2. Name: Locking CBL in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukaemia (part 1)