| Title: |
Histone deacetylase inhibition sensitizes p53-deficient B-cell precursor acute lymphoblastic leukemia to chemotherapy |
| Authors: |
Cox,Willem P.J.; Evander,Nils; van Ingen Schenau,Dorette S.; Stoll,Gawin R.; Anderson,Nadia; de Groot,Lieke; Grünewald,Kari J.T.; Hagelaar,Rico; Butler,Miriam; Kuiper, Roland P.; van der Meer,Laurens T.; van Leeuwen,Frank N.; Genetica; Cancer |
| Publication Year: |
2024 |
| Subject Terms: |
Hematology |
| Description: |
In pediatric acute lymphoblastic leukemia (ALL), mutations/deletions affecting the TP53 gene are rare at diagnosis. However, at relapse about 12% of patients show TP53 aberrations, which are predictive of a very poor outcome. Since p53-mediated apoptosis is an endpoint for many cytotoxic drugs, loss of p53 function frequently leads to therapy failure. In this study we show that CRISPR/Cas9-induced loss of TP53 drives resistance to a large majority of drugs used to treat relapsed ALL, including novel agents such as inotuzumab ozogamicin. Using a high-throughput drug screen, we identified the histone deacetylase inhibitor romidepsin as a potent sensitizer of drug responsiveness, improving sensitivity to all chemotherapies tested. In addition, romidepsin improved the response to cytarabine in TP53-deleted ALL cells in vivo. Together, these results indicate that the histone deacetylase inhibitor romidepsin can improve the efficacy of salvage therapies for relapsed TP53-mutated leukemia. Since romidepsin has been approved for clinical use in some adult malignancies, these findings may be rapidly translated to clinical practice. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text/plain |
| Language: |
English |
| ISSN: |
0390-6078 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/454205 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/454205 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.D2554A4 |
| Database: |
BASE |