Molecular signatures associated with venous thromboembolism in children with acute lymphoblastic leukemia

Background: Venous thromboembolism (VTE) is a frequent complication of childhood acute lymphoblastic leukemia (ALL).

Objectives: We aimed to identify molecular markers and signatures of leukemia microenvironment associated with VTE in childhood ALL, by dual-omics approach of gene expression (GEP) and DNA-methylation profiling.

Patients/methods: Eligible children were aged 1-21 years old with newly diagnosed ALL enrolled on the Dana Farber Cancer Institute 16-001 trial with available RNA sequencing data from bone marrow at diagnosis. Primary outcome was VTE requiring medical intervention, divided between early events (ET), within 6 weeks from ALL diagnosis, or late (LT) otherwise. We compared differential gene expression and DNA-methylation in children with and without VTE and in the subgroup of children with ETs. The DNA-methylation cis-regulation was explored by dual-omics integration. Functional gene set enrichment analyses were performed to assess dysregulated pathways associated with thrombosis. GEP-based signature for thrombosis-free interval was determined using Kaplan-Meier estimator and log-rank tests.

Results: We included 248 patients (median age: 7.5 years, 78% precursor B-cell ALL), of whom 56 (23%) developed VTE. Genes and metabolic pathways involved in coagulation, platelet activation and neutrophil extracellular trap formation (NETosis) were associated with ETs. Dual-omics analysis indicated that methylation reprogramming might be responsible for the over-expression of genes involved in NETosis and coagulation in patients with ETs. A prothrombotic gene signature, based on VWF, PF4 and CXCL8 expression, predicted thrombosis-free interval.

Conclusions: This suggests that gene markers and epigenetic regulation of the leukemic microenvironment are drivers of VTE, notably early events, in childhood ALL.