PXD041245

PXD041245 is an original dataset announced via ProteomeXchange.

Title	Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia
Description	Pharmacologic targeting of epigenetic protein complexes has shown significant in vitro responses in acute myeloid leukemia (AML). Early clinical trials in KMT2A-rearranged leukemia indicate rather transient responses and development of resistance. In an effort to define functional dependencies of KMT2A-fusions in AML, we identify the catalytic immunoproteasome subunit PSMB8 as a KMT2A-complex-specific vulnerability. Genetic and pharmacologic inactivation of PSMB8 results in impaired proliferation of murine and human leukemic cells while normal hematopoietic cells remain unaffected. Disruption of immunoproteasome function results in cellular enrichment of transcription factor BASP1, and consecutive repression of KMT2A-target genes. Pharmacologic targeting of PSMB8 improves efficacy of Menin-inhibitors, eradicates leukemia in primary human xenografts and shows preserved activity against Menin-inhibitor resistance mutations. This identifies and validates a cell-intrinsic mechanism whereby selective disruption of proteostasis results in altered transcription factor abundance and repression of oncogene-specific transcriptional networks. Therapeutic targeting of PSMB8-dependent transcription in combination with Menin-inhibition could thus eradicate KMT2A-complex driven AML.
HostingRepository	PRIDE
AnnounceDate	2024-01-26
AnnouncementXML	Submission_2024-01-26_09:10:13.090.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ashokkumar Jayavelu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-03-31 03:03:26	ID requested
⏵ 1	2024-01-26 09:10:13	announced

10.1186/s12943-023-01907-7;

Tub, í, o-Santamar, í, a N, Jayavelu AK, Schnoeder TM, Eifert T, Hsu CJ, Perner F, Zhang Q, Wenge DV, Hansen FM, Kirkpatrick JM, Jyotsana N, Lane SW, von Eyss B, Deshpande AJ, K, ü, hn MWM, Schwaller J, Cammann C, Seifert U, Ebstein F, Kr, ü, ger E, Hochhaus A, Heuser M, Ori A, Mann M, Armstrong SA, Heidel FH, Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia. Mol Cancer, 22(1):196(2023) [pubmed]

submitter keyword: AML, MLL-fusion, KMT2A, Immunoproteasome,Leukemia, Proteome

Dr.Ashok Kumar Jayavelu
contact affiliation	Proteomics and Cancer Cell Signaling, DKFZ Heidelberg
contact email	ak.jayavelu@dkfz-heidelberg.de
lab head
Ashokkumar Jayavelu
contact affiliation	Dept Proteomics and Signal Transduction, MaxPlanck Institute of Biochemistry
contact email	jayavelu@biochem.mpg.de
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/2024/01/PXD041245

PRIDE project URI

• PRIDE
  1. PXD041245
     1. Label: PRIDE project
     2. Name: Immunoproteasome function maintains oncogenic gene expression in KMT2A-complex driven leukemia