PXD029527

PXD029527 is an original dataset announced via ProteomeXchange.

Title	The dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia
Description	Eukaryotic ribosomal RNA carries diverse posttranscriptional modifications, among which the evolutionarily conserved 2’-O-methylation (2’-O-Me) occurs at more than 100 sites and is essential for ribosome biogenesis. Plasticity of 2´-O-Me in ribosomes and its functional consequences in human disease are not yet known. Here, we present the full rRNA 2’-O-Me landscape (ribomethylome) of human acute myeloid leukemia (AML) through profiling 94 patient samples as well as 21 normal hematopoietic samples of 5 different lineages. While interior modification sites in functional centers are persistently fully 2’-O-methylated in human AMLs, methylation on ribosome exterior sites is unprecedentedly dynamic. Higher 2’-O-methylation on exterior dynamic sites is associated with leukemia stem cell (LSC) signatures. Forced expression of enzymatically active but not of the catalytic defect 2’-O-methyltransferase FBL induces AML stemness and accelerates leukemogenesis in patient-derived xenografts. Mechanistically, ribomethylome dynamics shifted mRNA ribosome translation preferences. High rRNA 2’-O-Me enhances translation of amino acid transporters enriched in optimal codons and subsequently increases intra-cellular amino acid levels. Methylation on a single exterior modification site affects leukemia stem cell activity. The Guanosine 1447 on the small subunit ribosomal RNA is the most variable site in primary AMLs. Gm1447 is increased in leukemia stem cell populations compared to non-leukemogenic blast cells and AML specimens with higher Gm1447 are enriched for leukemia stem cell genes. Comparison of Gm1447high and Gm1447low ribosome structure solved by cryo-electron microscopy demonstrated disassociation of LYAR from Gm1447low ribosomes. Suppression of Gm1447 alone is sufficient to suppress translation of amino acid transporters, resulting in decreased cellular amino acid levels and leukemia stem cell activity. Taken together, our data reveal the dynamic FBL-mediated rRNA 2'-O-Me landscape as a novel epitranscriptomic level of control employed by leukemic stem cells and may enable new strategies to target human AML.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:36:10.060.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Daria Fijalkowska
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-02 08:47:28	ID requested
1	2023-03-10 19:51:40	announced
⏵ 2	2023-11-14 08:36:11	announced	2023-11-14: Updated project metadata.

Zhou F, Aroua N, Liu Y, Rohde C, Cheng J, Wirth AK, Fijalkowska D, G, ö, llner S, Lotze M, Yun H, Yu X, Pabst C, Sauer T, Oellerich T, Serve H, R, ö, llig C, Bornh, ä, user M, Thiede C, Baldus C, Frye M, Raffel S, Krijgsveld J, Jeremias I, Beckmann R, Trumpp A, M, ü, ller-Tidow C, A Dynamic rRNA Ribomethylome Drives Stemness in Acute Myeloid Leukemia. Cancer Discov, 13(2):332-347(2023) [pubmed]

submitter keyword: FBL, leukemia, nascent chain proteomics, rRNA, AHA, 2’-O-methylation, AML

Carsten Müller-Tidow
contact affiliation	Department of Internal Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany
contact email	Carsten.Mueller-tidow@med.uni-heidelberg.de
lab head
Daria Fijalkowska
contact affiliation	VIB-UGent Center for Medical Biotechnology
contact email	daria.fijalkowska@vib-ugent.be
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/2023/03/PXD029527

PRIDE project URI

• PRIDE
  1. PXD029527
     1. Label: PRIDE project
     2. Name: The dynamic rRNA ribomethylome drives stemness in acute myeloid leukemia