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Simple Summary T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, most often diagnosed in teenagers and young adults. Nowadays, patients are treated with chemotherapy or undergo a hematopoietic stem cell transplantation. This can cause many short- and long-term side-effects and relapse still occurs. Therefore, finding less toxic anti-lymphoma therapies is hoped for. One epidrug of interest is decitabine, a DNA hypomethylating agent that targets the aberrant DNA methylation profile, which previously was FDA-approved for AML and MDS. With the results in this manuscript, we especially hope to provide pre-clinical proof that is necessary to include decitabine as a therapeutic agent in clinical trials for the treatment of T-LBL. Moreover, with the reported downstream effects of decitabine treatment, we hope to further increase the understanding of the working mechanisms of decitabine, which could ultimately result in better treatment protocols and associated biomarkers for T-LBL patients. 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.

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p &lt, 5 &times, 10&minus, 8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p &lt, 1 &times, 6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%, p = 3.95 &times, 7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%, p = 4.34 &times, 7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.