 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Dec 07, 2023 |
| Title |
DHODH: A promising target in the treatment of T-Acute Lymphoblastic Leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Children with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. Multiple lines of evidence point towards the enzyme dihydroorotate dehydrogenase (DHODH) as a metabolic vulnerability in dysregulated and malignant T‑cells. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis (e.g., uridine, cytidine). Therefore, inhibiting DHODH via small molecule inhibitors (DHODHi) rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death.
T‑lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation following DHODHi. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T‑ALL. Additionally, we have identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, have changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. We hope these changes point to a metabolic vulnerability that may distinguish them from normal T-cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.
|
| |
|
| Overall design |
Transcriptional profiling of Jurkat cells harvested at 8 and 24 hours following treatment with 1 uM Brequinar (BRQ) vs. DMSO in triplicate.
|
| |
|
| Contributor(s) |
Sexauer A, Alexe G |
| Citation(s) |
37648673 |
| Submission date |
Oct 28, 2022 |
| Last update date |
Dec 07, 2023 |
| Contact name |
Gabriela Alexe |
| E-mail(s) |
galexe@broadinstitute.org
|
| Organization name |
Broad Institute
|
| Department |
Computational Biology and Bioinformatics
|
| Street address |
415 Main St.
|
| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (12)
|
| GSM6690492 |
Jurkat cells, DMSO, 8 hours, replicate 1 |
| GSM6690493 |
Jurkat cells, DMSO, 8 hours, replicate 2 |
| GSM6690494 |
Jurkat cells, DMSO, 8 hours, replicate 3 |
| GSM6690495 |
Jurkat cells, 1 uM Brequinar, 8 hours, replicate 1 |
| GSM6690496 |
Jurkat cells, 1 uM Brequinar, 8 hours, replicate 2 |
| GSM6690497 |
Jurkat cells, 1 uM Brequinar, 8 hours, replicate 3 |
| GSM6690498 |
Jurkat cells, DMSO, 24 hours, replicate 1 |
| GSM6690499 |
Jurkat cells, DMSO, 24 hours, replicate 2 |
| GSM6690500 |
Jurkat cells, DMSO, 24 hours, replicate 3 |
| GSM6690501 |
Jurkat cells, 1 uM Brequinar, 24 hours, replicate 1 |
| GSM6690502 |
Jurkat cells, 1 uM Brequinar, 24 hours, replicate 2 |
| GSM6690503 |
Jurkat cells, 1 uM Brequinar, 24 hours, replicate 3 |
|
| Relations |
| BioProject |
PRJNA895327 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE216753_RNASeq_all_samples_counts.txt.gz |
849.3 Kb |
(ftp)(http) |
TXT |
| GSE216753_RNASeq_all_samples_log2TPMplus1.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
Less...
More...