PXD053512-1

PXD053512 is an original dataset announced via ProteomeXchange.

Title	Longitudinal omics data and preclinical treatment identify proteasome inhibition as therapy for ibrutinib-resistant CLL
Description	Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival of CLL patients, nevertheless acquired drug resistance represents a major challenge the molecular mechanisms of which have not been fully elucidated yet. To overcome this limitation, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive salvage treatment option for CLL patients resistant or refractory to ibrutinib.
HostingRepository	PRIDE
AnnounceDate	2024-12-10
AnnouncementXML	Submission_2024-12-10_04:45:37.250.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gianluca Sigismondo
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-29 07:12:50	ID requested
⏵ 1	2024-12-10 04:45:37	announced

Dataset with its publication pending

submitter keyword: CLL, BTKi, carfilzomib, proteasome, quantitative proteomics, transcriptomics, ibrutinib-resistance

Martina Seiffert
contact affiliation	Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
contact email	m.seiffert@dkfz.de
lab head
Gianluca Sigismondo
contact affiliation	DKFZ
contact email	gianluca.sigismondo@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/12/PXD053512

PRIDE project URI

• PRIDE
  1. PXD053512
     1. Label: PRIDE project
     2. Name: Longitudinal omics data and preclinical treatment identify proteasome inhibition as therapy for ibrutinib-resistant CLL