PXD041273

PXD041273 is an original dataset announced via ProteomeXchange.

Title	DUX4-r exerts a neomorphic activity that depens on GTF2I in acute lymphoblastic leukemia
Description	Translocations producing rearranged versions of the transcription factor DUX4 (DUX4-r) are one of the most frequent causes of B-cell acute lymphoblastic leukemia (B-ALL). DUX4-r retains the DNA binding domain of wt DUX4, but is truncated on the C-terminal transcription activation domain. The precise mechanism through which DUX4-r causes leukemia is unknown and no targeted therapy is currently available. We found that the rearrangement leads to both a loss and a gain of function in DUX4-r. Loss of CBP/EP300 transcriptional co-activators interaction and inability to bind and activate repressed chromatin. Gain of interaction with the transcription factor GTF2I, which redirects DUX4-r toward leukemogenic targets. Importantly, this neomorphic activity exposes an Achilles' heel whereby DUX4-r positive leukemia cells are exquisitely sensitive to GTF2I targeting, which inhibits DUX4-r leukemogenic activity. Our work elucidates the molecular mechanism through which DUX4-r causes leukemia and suggest a possible therapeutic avenue tailored to this B-ALL subtype.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:03:14.697.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Davide Gabellini
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-02 00:21:42	ID requested
1	2023-09-16 09:54:37	announced
2	2023-11-14 08:54:29	announced	2023-11-14: Updated project metadata.
⏵ 3	2024-10-22 06:03:15	announced	2024-10-22: Updated project metadata.

10.1126/SCIADV.ADI3771;

submitter keyword: proteomics, leukemia,Affinity purification

Davide Gabellini
contact affiliation	San Raffaele Scientific Institute
contact email	labgabellini@gmail.com
lab head
Davide Gabellini
contact affiliation	San Raffaele Scientific Institute
contact email	labgabellini@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD041273
     1. Label: PRIDE project
     2. Name: DUX4-r exerts a neomorphic activity that depens on GTF2I in acute lymphoblastic leukemia