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Pre-clinical evaluation of the hypomethylating agent decitabine for the treatment of t-cell lymphoblastic lymphoma
Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
Taghon Laboratory, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Normal and Malignant Hematopoiesis Laboratory, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Taghon Laboratory, Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
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2023 (English)In: Cancers, ISSN 2072-6694, Vol. 15, no 3, article id 647Article in journal (Refereed) Published
Abstract [en]

T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10–20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine. We evaluated the anti-lymphoma properties and downstream effects of decitabine, using patient derived xenograft (PDX) models. Decitabine treatment resulted in prolonged lymphoma-free survival in all T-LBL PDX models, which was associated with downregulation of the oncogenic MYC pathway. However, some PDX models showed more benefit of decitabine treatment compared to others. In more sensitive models, differentially methylated CpG regions resulted in more differentially expressed genes in open chromatin regions. This resulted in stronger downregulation of cell cycle genes and upregulation of immune response activating transcripts. Finally, we suggest a gene signature for high decitabine sensitivity in T-LBL. Altogether, we here delivered pre-clinical proof of the potential use of decitabine as a new therapeutic agent in T-LBL.

Place, publisher, year, edition, pages
MDPI, 2023. Vol. 15, no 3, article id 647
Keywords [en]
decitabine, DNA methylation, T-LBL
National Category
Hematology
Identifiers
URN: urn:nbn:se:umu:diva-205009DOI: 10.3390/cancers15030647ISI: 000933785600001Scopus ID: 2-s2.0-85147801370OAI: oai:DiVA.org:umu-205009DiVA, id: diva2:1738746
Funder
EU, European Research Council, StG-639784Swedish Childhood Cancer Foundation, PR 2021-0049Swedish Cancer Society, 20-1053-PJThe Kempe Foundations, JCK-1833EU, Horizon 2020Available from: 2023-02-22 Created: 2023-02-22 Last updated: 2024-03-26Bibliographically approved

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Landfors, MattiasDegerman, Sofie

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