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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 27, 2024 |
| Title |
Alpha-ketoglutarate dehydrogenase is a therapeutic vulnerability in acute myeloid leukemia [KL974_shOGDH] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Perturbations in intermediary metabolism contribute to the pathogenesis of acute myeloid leukemia (AML) and can produce therapeutically actionable dependencies. Here, we probed whether alpha-ketoglutarate (aKG) metabolism represents a specific vulnerability in AML. Using functional genomics, metabolomics, and mouse models, we identified the aKG dehydrogenase complex, which catalyzes the conversion of aKG to succinyl CoA, as a molecular dependency across multiple models of adverse-risk AML. Inhibition of 2-oxoglutarate dehydrogenase (OGDH), the E1 subunit of the aKG dehydrogenase complex, impaired AML progression and drove differentiation. Mechanistically, hindrance of aKG flux through the tricarboxylic acid (TCA) cycle resulted in rapid exhaustion of aspartate pools and blockade of de novo nucleotide biosynthesis, while cellular bioenergetics was largely preserved. Additionally, increased aKG levels following OGDH inhibition impacted the biosynthesis of other critical amino acids. Thus, this work has identified a previously undescribed, functional link between certain TCA cycle components and nucleotide biosynthesis enzymes across AML. This metabolic node may serve as a cancer-specific vulnerability amenable to therapeutic targeting in AML and perhaps in other cancers with similar metabolic wiring.
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| Overall design |
RNA sequencing of murine p53-mutant AML cell lines was perfored at days 0, 2, and/or 4 after induction of the indicated BFP-linked shRNAs with doxycycline. Two independent shRNAs targeting Ogdh (shOgdh346 and shOgdh2081) and a control shRNA (shRen713) were used. Sorted, induced (BFPplus) cells are included for all shRNAs. Undinduced (BFPmin) cells at each timepoint are included for control samples.
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| Contributor(s) |
Millman SE, Chaves-Perez A, Janaki-Raman S, Ho Y, Morris IV JP, Narendra V, Chen C, Jackson BT, Yashinskie JJ, Mezzadra R, Devine TI, Barthet VA, Saoi M, Baslan T, Tian S, Sachs Z, Finley LS, Cross JR, Lowe SW |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Nov 27, 2024 |
| Last update date |
Nov 27, 2024 |
| Contact name |
Yu-Jui Ho |
| E-mail(s) |
[email protected]
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| Organization name |
Memorial Sloan Kettering Cancer Center
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| Department |
Cancer Biology & Genetics Program
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| Street address |
417 E 68th St
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| City |
New York |
| State/province |
New York |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (14)
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| GSM8653869 |
Murine AML, control shRNA, D0, rep1 |
| GSM8653870 |
Murine AML, control shRNA, D2, uninduced sorted, rep1 |
| GSM8653871 |
Murine AML, control shRNA, D2, induced sorted, rep1 |
| GSM8653872 |
Murine AML, control shRNA, D4, uninduced sorted, rep1 |
| GSM8653873 |
Murine AML, control shRNA, D4, induced sorted, rep1 |
| GSM8653874 |
Murine AML, control shRNA, D0, rep2 |
| GSM8653875 |
Murine AML, control shRNA, D2, uninduced sorted, rep2 |
| GSM8653876 |
Murine AML, control shRNA, D2, induced sorted, rep2 |
| GSM8653877 |
Murine AML, control shRNA, D4, induced sorted, rep2 |
| GSM8653878 |
Murine AML, control shRNA, D4, uninduced sorted, rep2 |
| GSM8653879 |
Murine AML, OGDH shRNA1, D4, induced sorted, rep1 |
| GSM8653880 |
Murine AML, OGDH shRNA1, D4, induced sorted, rep2 |
| GSM8653881 |
Murine AML, OGDH shRNA2, D4, induced sorted, rep1 |
| GSM8653882 |
Murine AML, OGDH shRNA2, D4, induced sorted, rep2 |
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| Relations |
| BioProject |
PRJNA1191400 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE282977_Millman_KL974_OGDH_RNASeq.cnt.csv.gz |
4.4 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
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