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| Status |
Public on Aug 17, 2020 |
| Title |
Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The combination of venetoclax with azacitidine (ven/aza) has recently emerged as a promising regimen for acute myeloid leukemia (AML), with approximately 70% of newly diagnosed patients achieving complete remission (CR). However, 30% of newly diagnosed and nearly all relapsed patients do not achieve CR with ven/aza. Mechanistically, we previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. In the present study we demonstrate that resistance to ven/aza occurs as a consequence of up-regulated fatty acid oxidation (FAO), which occurs either as an intrinsic property of RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism into the TCA cycle, thereby rendering ven/aza ineffective. Importantly, we show that pharmacological inhibition of FAO via use of MCL-1 or CPT1 inhibitor drugs restores targeting of ven/aza resistant AML stem cells. Based on these findings we propose that inhibition of FAO is a potential therapeutic strategy to address ven/aza resistance.
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| Overall design |
RNA was isolated from freshly sorted primary AML cells and subjected to RNA-seq analysis.
|
| Web link |
https://doi.org/10.1038/s43018-020-00126-z
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| |
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| Contributor(s) |
Stevens B, Becker M, Pei S, Jordan CT |
| Citation missing |
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| |
| Submission date |
Aug 10, 2020 |
| Last update date |
Feb 24, 2021 |
| Contact name |
Brett Stevens |
| E-mail(s) |
brett.stevens@ucdenver.edu
|
| Phone |
3037248231
|
| Organization name |
University of Colorado
|
| Lab |
Jordan Lab
|
| Street address |
12700 E 19th Avenue, Rm 10440C
|
| City |
Aurora |
| State/province |
CO |
| ZIP/Postal code |
80045 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
|
| Samples (24)
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| Relations |
| BioProject |
PRJNA656302 |
| SRA |
SRP276958 |
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