Back to Search
Start Over
Targeting leukemia-specific dependence on the de novo purine synthesis pathway
- Source :
- Leukemia. 36:383-393
- Publication Year :
- 2021
- Publisher :
- Springer Science and Business Media LLC, 2021.
-
Abstract
- Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
- Subjects :
- Cancer Research
Carboxy-Lyases
Apoptosis
Mice, SCID
Biology
Gene Expression Regulation, Enzymologic
Mice
Mice, Inbred NOD
hemic and lymphatic diseases
Tumor Cells, Cultured
medicine
Animals
Humans
CRISPR
Enzyme Inhibitors
neoplasms
Cell Proliferation
DNA synthesis
Gene Expression Regulation, Leukemic
Cas9
Myeloid leukemia
Hematology
medicine.disease
Xenograft Model Antitumor Assays
Mice, Inbred C57BL
De novo synthesis
Leukemia, Myeloid, Acute
Leukemia
Oncology
Purines
Cell culture
Cancer research
CRISPR-Cas Systems
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 14765551 and 08876924
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....b80c2aab609332fe7ddc377394f377cc