PXD017147

PXD017147 is an original dataset announced via ProteomeXchange.

Title	IL7R mutational activation can initiate Ph-like and PAX5 P80R precursor B-cell acute lymphoblastic leukemia
Description	Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemia stage in which B-cell precursors display self-renewal ability, initiating precursor B-ALL that resembles PAX5 P80R or Ph-like human leukemia. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving both JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are novel treatment avenues for IL-7R-related cases. Our model, a unique resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
HostingRepository	PRIDE
AnnounceDate	2023-04-11
AnnouncementXML	Submission_2023-04-11_06:09:13.530.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	AndrewHowden
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2020-01-16 03:48:33	ID requested
1	2021-11-02 03:52:01	announced
⏵ 2	2023-04-11 06:09:14	announced	2023-04-11: Updated project metadata.

Almeida ARM, Neto JL, Cachucho A, Euz, é, bio M, Meng X, Kim R, Fernandes MB, Raposo B, Oliveira ML, Ribeiro D, Fragoso R, Zenatti PP, Soares T, de Matos MR, Corr, ê, a JR, Duque M, Roberts KG, Gu Z, Qu C, Pereira C, Pyne S, Pyne NJ, Barreto VM, Bernard-Pierrot I, Clappier E, Mullighan CG, Grosso AR, Yunes JA, Barata JT, mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. Nat Commun, 12(1):7268(2021) [pubmed]

submitter keyword: acute lymphoblastic leukemia,B cells

Professor João T.Barata
contact affiliation	Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
contact email	joao_barata@medicina.ulisboa.pt
lab head
AndrewHowden
contact affiliation	University of Dundee
contact email	a.howden@dundee.ac.uk
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/2021/11/PXD017147

PRIDE project URI

• PRIDE
  1. PXD017147
     1. Label: PRIDE project
     2. Name: IL7R mutational activation can initiate Ph-like and PAX5 P80R precursor B-cell acute lymphoblastic leukemia