PXD009020

PXD009020 is an original dataset announced via ProteomeXchange.

Title	Pathogenesis of dominant-negative mutant GFI1B and associated proteomic abnormalities in megakaryocytes and platelets
Description	Dominant-negative mutations in transcription factor Growth Factor Independence-1B (GFI1B) cause a bleeding disorder characterized by a plethora of megakaryocyte and platelet abnormalities. The deregulated molecular mechanisms and pathways are unknown. Here we show that normal and mutant GFI1B interacted most strongly with the LSD1-RCOR-HDAC corepressor complex in megakaryoblasts. Sequestration of this complex by mutant GFI1B and chemical separation of GFI1B from LSD1 induced abnormalities in normal megakaryocytes comparable to those seen in patients. Megakaryocytes derived from GFI1B-mutant induced pluripotent stem cells (iPSC) also phenocopied abnormalities seen in patients. Proteome studies on normal and mutant iPSC-derived megakaryocytes identified a multitude of deregulated pathways downstream of mutant GFI1B. Proteome studies on primary normal and GFI1B-mutant platelets showed reduced expression of proteins implicated in platelet function, and sustained expression of proteins normally downregulated during megakaryocyte differentiation. Thus, GFI1B regulates a broad developmental program during megakaryopoiesis. Mutant GFI1B deregulates this program through LSD1-RCOR-HDAC sequestering.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:43:16.141.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Johanna Koornneef
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetic acid derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2018-02-23 03:30:37	ID requested
1	2019-01-25 06:01:50	announced
⏵ 2	2024-10-22 04:43:24	announced	2024-10-22: Updated project metadata.

10.3324/haematol.2018.194555;

van Oorschot R, Hansen M, Koornneef JM, Marneth AE, Bergevoet SM, van Bergen MGJM, van Alphen FPJ, van der Zwaan C, Martens JHA, Vermeulen M, Jansen PWTC, Baltissen MPA, Gorkom BAPL, Janssen H, Jansen JH, von Lindern M, Meijer AB, van den Akker E, van der Reijden BA, mutation and its affected pathways in megakaryocytes and platelets. Haematologica, 104(7):1460-1472(2019) [pubmed]

curator keyword: Biomedical

submitter keyword: megakaryocytes, LSD1, bleeding disorder, LC-MS,Proteomics, platelet, GFI1B

Alexander Meijer
contact affiliation	Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands
contact email	s.meijer@sanquin.nl
lab head
Johanna Koornneef
contact affiliation	Sanquin Research, Amsterdam, The Netherlands
contact email	a.koornneef@sanquin.nl
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/2019/01/PXD009020

PRIDE project URI

• PRIDE
  1. PXD009020
     1. Label: PRIDE project
     2. Name: Pathogenesis of dominant-negative mutant GFI1B and associated proteomic abnormalities in megakaryocytes and platelets