PXD022411

PXD022411 is an original dataset announced via ProteomeXchange.

Title	Central nervous system involvement of acute lymphoblastic leukemia depends on mRNA translation and complement component 3
Description	Central nervous system (CNS) dissemination of B-precursor acute lymphoblastic leukemia (B-ALL) has a poor prognosis and remains a therapeutic challenge with few recent advances in therapy. Leptomeningeal disease is particularly common in the high risk subgroup of KMT2A-rearranged B-ALL (KMT2A-r B-ALL). Here we performed transcriptional and proteomic profiling of leukemia cells from bone marrow (BM) and CNS-disseminated disease in KMT2A-r B-ALL xenografts. CNS disease exhibited stemness traits and metabolic reprogramming previously associated with chemotherapy resistance. Genes governing mRNA translation were upregulated in CNS samples, a finding confirmed in cohorts of KMT2A-r B-ALL patients with CNS involvement. This upregulation was functionally important for CNS disease as the mRNA translational inhibitor omacetaxine mepesuccinate (OMA) significantly reduced leptomeningeal disease burden in xenografts. Proteomic analysis demonstrated greater abundance of secreted proteins in CNS infiltrating cells including complement component 3 (C3), a known driver of leptomeningeal metastasis in solid tumours, pointing to a convergent mechanism for this route of metastasis in multiple cancers. Pharmacological inhibition of C3a signaling suppressed CNS dissemination, whereas C3a receptor activation increased CNS disease. Overall, our study identifies mRNA translation and a set of secreted proteins as key mediators of CNS dissemination in KMT2A-r B-ALL. Therapeutic targeting of these dependencies represents a novel approach to prevent or treat leptomeningeal disease.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:35:59.432.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Erwin Schoof
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-11-06 08:30:38	ID requested
1	2023-03-10 19:40:30	announced
⏵ 2	2023-11-14 08:36:00	announced	2023-11-14: Updated project metadata.

Vanner RJ, Dobson SM, Gan OI, McLeod J, Schoof EM, Grandal I, Wintersinger JA, Garcia-Prat L, Hosseini M, Xie SZ, Jin L, Mbong N, Voisin V, Chan-Seng-Yue M, Kennedy JA, Waanders E, Morris Q, Porse B, Chan SM, Guidos CJ, Danska JS, Minden MD, Mullighan CG, Dick JE, Multiomic Profiling of Central Nervous System Leukemia Identifies mRNA Translation as a Therapeutic Target. Blood Cancer Discov, 3(1):16-31(2022) [pubmed]

submitter keyword: LC-MS, leukemia, LFQ

John Dick
contact affiliation	Princess Margaret Cancer Centre, University Health Network, M5G 1L7, Toronto, Canada
contact email	jdick@uhnres.utoronto.ca
lab head
Erwin Schoof
contact affiliation	Technical University of Denmark
contact email	erws@dtu.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD022411
     1. Label: PRIDE project
     2. Name: Central nervous system involvement of acute lymphoblastic leukemia depends on mRNA translation and complement component 3