Pre-clinical evaluation of the hypomethylating agent decitabine for the treatment of T-cell acute lymphoblastic lymphoma

ABSTRACT: T-cell acute lymphoblastic lymphoma (T-LBL) is a rare and aggressive blood cancer, most often diagnosed in teenagers and young adults. Patients are usually treated with intensive chemotherapy which causes many side effects and relapse still occurs. Therefore, the search toward less toxic anti-leukemic therapies is ongoing. In line with this, we here focused on targeting a recently described perturbed DNA methylation profile in T-LBL. This aberrantly methylated DNA can serve as a new therapeutic target for DNA hypomethylating epidrugs like decitabine. We evaluated the anti-leukemic properties and downstream effects of decitabine using T-LBL patient derived xenograft (PDX) models. Interestingly, decitabine treatment resulted in prolonged leukemia-free survival in all T-LBL PDX models, which was mediated by i.a. downregulation of the oncogenic MYC pathway. However, some PDX models had more benefit of being treated with decitabine compared to others. Remarkably, differentially methylated CpG islands regions resulted in significantly more differentially expressed genes in open chromatin in the more sensitive group. This resulted in i.a. stronger downregulation of cell cycle genes and upregulation of immune response activating genes. Furthermore, we suggested a gene signature for high decitabine sensitivity. In conclusion, we delivered pre-clinical data of the potential of decitabine to act as a new therapeutic agent in T-LBL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218060 | GEO | 2023/03/02

REPOSITORIES: GEO