PXD041875

PXD041875 is an original dataset announced via ProteomeXchange.

Title	NG2 is a target gene of MLL-AF4 that underlies glucocorticoid resistance in infant MLL-rearranged B-ALL by regulating NR3C1 expression through interaction with FLT3
Description	B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer, with long-term overall survival rates of 80%. However, B-ALL harboring rearrangements of the MLL gene (also known as KTM2A), hereinafter termed MLLr B-ALL, is frequently seen in infants and is associated with poor 5-year survival (<30%), frequent relapses, and refractoriness to glucocorticoids (GC). GC are an essential part of the treatment backbone for B-ALL and GC resistance is a major clinical predictor of poor outcome. Unraveling the mechanisms of GC resistance in MLLr B-ALL is, therefore, crucial to guide therapeutic strategies that deepen response after induction therapy. Neuron-glial antigen-2 (NG2) expression is a hallmark of MLLr B-ALL and is minimally expressed in healthy hematopoietic cells. We recently reported that NG2 expression is associated with poor prognosis and that anti-NG2 immunotherapy strongly reduces/delays relapse in xenograft models of MLLr B-ALL. However, despite its contribution to MLLr B-ALL pathogenesis and its diagnostic utility, the role of NG2 in MLLr-mediated leukemogenesis/chemoresistance remains elusive. We show here that NG2 is an epigenetically regulated direct target gene of the leukemic MLL-AF4 fusion protein. NG2 negatively regulates the expression of the GC receptor NR3C1, conferring GC chemoresistance to MLLr B-ALL cells in vitro and in vivo. Mechanistically, NG2 interacts with FLT3 to render ligand-independent activation of FLT3 signaling (a hallmark of MLLr B-ALL) and downregulation of NR3C1 via AP-1-mediated transrepression. Collectively, our study elucidates the role of NG2 in GC resistance in MLLr B-ALL through a FLT3/AP-1-mediated downregulation of NR3C1, providing novel therapeutic avenues for MLLr B-ALL.
HostingRepository	PRIDE
AnnounceDate	2024-07-12
AnnouncementXML	Submission_2024-07-12_03:36:33.598.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Narcis Fuentes
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-28 06:17:02	ID requested
⏵ 1	2024-07-12 03:36:33	announced

Dataset with its publication pending

submitter keyword: NR3C1, AP-1, MLL-AF4, FLT3, infant B-ALL, glucocorticoid resistance,NG2

Prof. Pablo Menendez
contact affiliation	Pablo Menéndez, ICREA Research Professor Stem cell biology, developmental leukemia & immunotherapy Lab Josep Carreras Leukaemia Research Institute Associate Professor - School of Medicine - University of Barcelona Carrer casanova 143. Barcelona 08036. Spain Tel. (+34) 932414287
contact email	pmenendez@carrerasresearch.org
lab head
Narcis Fuentes
contact affiliation	Institute Josep Carreras
contact email	nfernandez@carrerasresearch.org
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/2024/07/PXD041875

PRIDE project URI

• PRIDE
  1. PXD041875
     1. Label: PRIDE project
     2. Name: NG2 is a target gene of MLL-AF4 that underlies glucocorticoid resistance in infant MLL-rearranged B-ALL by regulating NR3C1 expression through interaction with FLT3