PXD017147-1

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	2021-11-02
AnnouncementXML	Submission_2021-11-02_03:52:01.369.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andrew Howden
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated 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.

Dataset with its publication pending

submitter keyword: B cells, acute lymphoblastic leukemia

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
Andrew Howden
contact affiliation	University of Dundee
contact email	a.howden@dundee.ac.uk
dataset submitter

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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