PXD008307

PXD008307 is an original dataset announced via ProteomeXchange.

Title	Tandem mass tag (TMT) quantitative proteomics of human acute myeloid leukaemia (AML)
Description	The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate11,12. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mutAML. Gene sets characteristic for IDHmut AML13 were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1highAML showed robust enrichment for leukaemia stem-cell signatures14,15, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA–BCAT1–αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML.
HostingRepository	PRIDE
AnnounceDate	2019-12-19
AnnouncementXML	Submission_2019-12-19_00:30:15.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jenny Hansson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2017-11-28 00:12:46	ID requested
1	2017-11-28 03:46:42	announced
2	2017-11-29 02:45:50	announced	Updated project metadata.
3	2019-12-06 08:26:13	announced	2019-12-06: Updated project metadata.
4	2019-12-06 08:33:01	announced	2019-12-06: Updated project metadata.
5	2019-12-09 06:50:41	announced	2019-12-09: Updated project metadata.
⏵ 6	2019-12-19 00:43:00	announced	2019-12-19: Updated project metadata.

Raffel S, Falcone M, Kneisel N, Hansson J, Wang W, Lutz C, Bullinger L, Poschet G, Nonnenmacher Y, Barnert A, Bahr C, Zeisberger P, Przybylla A, Sohn M, T, ö, njes M, Erez A, Adler L, Jensen P, Scholl C, Fr, ö, hling S, Cocciardi S, Wuchter P, Thiede C, Fl, ö, rcken A, Westermann J, Ehninger G, Lichter P, Hiller K, Hell R, Herrmann C, Ho AD, Krijgsveld J, Radlwimmer B, Trumpp A, KG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature, 551(7680):384-388(2017) [pubmed]

curator keyword: Biomedical

submitter keyword: Human, AML, leukemic stem cells, LC-MSMS, TMT

Jenny Hansson
contact affiliation	Department of Laboratory Medicine, Lund University, Sweden
contact email	jenny.hansson@med.lu.se
lab head
Jenny Hansson
contact affiliation	Lund University
contact email	jehansson@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD008307
     1. Label: PRIDE project
     2. Name: Tandem mass tag (TMT) quantitative proteomics of human acute myeloid leukaemia (AML)