Abstract 3897: Ribosomal translational regulation is a potential mechanism for leukemia-related thrombo-embolic event in childhood acute lymphoblastic leukemia
Authors: Pelland-Marcotte Marie-Claude , Rémy Meredith Michelle , Ma Yan , Liu Jessica , Jimenez-Cortes Camille , Sontag Thomas , Caron Maxime , Saint-Onge Pascal , Langlois Sylvie , Joly-Beauparlant Charles , Sinnett Daniel , Droit Arnaud , Tran Thai Hoa , Santiago Raoul 
Published: June 2022

Abstract
Introduction: Thrombo-embolic event (TE) is a frequent complication of childhood acute lymphoblastic leukemia (cALL) and is associated with reduced survival. Overexpression of podoplanin or coagulome genes and coagulation pathway activation have been identified in cancer-induced TE but the role of leukemia environment in TE occurrence has not been fully elucidated in ALL. We assessed whether leukemia gene expression (GE) signature at diagnosis was associated with TE development in cALL.
Methods: We included children aged 0-18 years old (y.o.), from two hospitals, with newly diagnosed ALL and available RNA sequencing data from bone marrow at diagnosis. The primary outcome was the occurrence of grade ≥2 TE during ALL therapy using the Ponte Di Legno Working Group classification. TEs were classified as early (ET) if they occurred within 6 weeks from treatment start, or late (LT) otherwise. We compared differential gene expression (DE) in children with and without TE, adjusted for age (&lt;10 or ≥10 y.o.) and ALL type (T or B-ALL). A secondary analysis stratified children between ET, LT and no TE. Gene set enrichment analysis (GSEA) was performed on KEGG and gene ontology (GO) databases. DE with absolute fold change ≥2 and p-values &lt;0.05 were considered significant.
Results: We included 80 patients (median age: 5 years [interquartile range, IQR: 3-11 years], 53% male, 83% precursor B-cell ALL) of whom 19 (23.8%) developed a TE (7 ET and 12 LT) at a median of 76 days (IQR: 31-133 days) following cancer diagnosis. Patients with TE were more likely to be ≥10 y.o., while other demographic and clinical characteristics were similar. No genes from the coagulome, podoplanin or Hallmark coagulation pathways were differentially expressed in children with and without TE. The KEGG Ribosome pathway was the most upregulated pathway in the group with TE (normalized enrichment score (NES) = 2.35, adjusted p-value= 0.012) and ET (NES = 2.63, adjusted p-value &lt; 0.001). LT was not significantly associated with ribosome pathway dysregulation. Interestingly, prior reports identified functional enrichment in ribosomal pathway as a biomarker for venous TE. A heatmap classification for ribosomal genes revealed 3 distinct signatures: ribosomal downregulation, moderate and high ribosomal activation. High ribosomal activation profile was seen in 6/7 ET and 9/12 LT, corresponding to a positive and negative predictive value of 0.55 and 0.92 for TE, respectively.
Conclusion: TEs in cALL were not associated with dysregulation in coagulation pathways or podoplanin gene at the RNA level. However, ribosomal translational pathway was highly upregulated in the group with thrombosis, particularly with ET. Dysregulation of posttranscriptional machinery might explain the pro-thrombotic effect of leukemia environment in cALL and warrants further investigation including proteomic exploration.
Citation Format: Marie-Claude Pelland-Marcotte, Meredith Michelle Rémy, Yan Ma, Jessica Liu, Camille Jimenez-Cortes, Thomas Sontag, Maxime Caron, Pascal Saint-Onge, Sylvie Langlois, Charles Joly-Beauparlant, Daniel Sinnett, Arnaud Droit, Thai Hoa Tran, Raoul Santiago. Ribosomal translational regulation is a potential mechanism for leukemia-related thrombo-embolic event in childhood acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3897.