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

IF 5.5 2区 医学 Q1 HEMATOLOGY
Marie-Claude Pelland-Marcotte, Anas Belaktib, Arnaud Droit, Meredith Michelle Remy, Jeyani George Clement, Stéphanie Bianco, Yan Ma, Jessica Liu, Lara Herrmann, Virgile Raufaste-Cazavieille, Charles Joly-Beauparlant, Loïc Mangnier, Mickael Leclercq, Thomas Sontag, Maxime Caron, Pascal St-Onge, Sylvie Langlois, Victoria Koch, Yael Flamand, Daniel Sinnett, Lewis Silverman, Thai Hoa Tran, Raoul Santiago
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引用次数: 0

Abstract

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.

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来源期刊
Journal of Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis 医学-外周血管病
CiteScore
24.30
自引率
3.80%
发文量
321
审稿时长
1 months
期刊介绍: The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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