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| Status |
Public on Nov 08, 2017 |
| Title |
Role of Branched Chain Amino Acid Transaminase 1 (BCAT1) in Acute Myeloid Leukemia [methylation_MOLM13_BCAT1-OE_10weeks] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
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| Summary |
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. By performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem cell (LSC) and non-LSC populations, we found the BCAA pathway enriched and BCAT1 overexpressed in LSCs. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Next to its role in the tricarboxylic acid (TCA) cycle αKG is an essential co-factor for αKG-dependent dioxygenases such as EGLN1 and the TET family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG leading to HIF1a protein degradation mediated by EGLN1. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. In contrast, overexpression (OE) of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation via altered TET activity. BCAT1high AMLs displayed a DNA hypermethylation phenotype similar to cases carrying mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate. High levels of BCAT1 strongly correlate with shorter overall survival in IDHwtTET2wt, but not IDHmut or TET2mut AMLs. Gene sets characteristic for IDHmut AMLs were enriched in IDHwtTETwtBCAT1high patient samples. BCAT1high AMLs showed robust enrichment for LSC signatures and paired sample analysis revealed a significant increase of BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1a stability and regulation of the epigenomic landscape. Our results suggest the BCAA-BCAT1-αKG pathway as a therapeutic target to compromise LSC function in IDHwtTET2wt AML patients.
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| Overall design |
MOLM13 cell lines were lentivirally transduced with an inducible BCAT1 overexpression construct and selected for transduced cells. Overexpression was induced with Doxycyclin for 10 weeks and cells were lysed and RNA was extracted.
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| Contributor(s) |
Raffel S, Falcone M |
| Citation(s) |
29144447 |
| |
| Submission date |
Jul 04, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Simon Raffel |
| E-mail(s) |
[email protected]
|
| Organization name |
German Cancer Research Center
|
| Street address |
INF 280
|
| City |
Heidelberg |
| ZIP/Postal code |
69120 |
| Country |
Germany |
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| Platforms (1) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE100784 |
Role of Branched Chain Amino Acid Transaminase 1 (BCAT1) in Acute Myeloid Leukemia |
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| Relations |
| BioProject |
PRJNA393036 |
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