Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia

Abstract

• Variants in genes important for mesenchymal stem cell differentiation influence the risk of osteonecrosis in children with ALL under 10 years old.• Variants in genes in the glutamate signaling pathway influence osteonecrosis in children with ALL regardless of age.Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL [OR 10.8] in the discovery and replication cohorts, respectively). In a meta-analysis, the BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the significance threshold of <5 3 10 28. Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and analysis of annotated genes demonstrated enrichment in glutamate receptor and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis. (Blood. 2016;127(5):558-564)

Osteonecrosis in children with acute lymphoblastic leukemia

“…6,9,[65][66][67][68] Polymorphisms in the plasminogen activator inhibitor-1 (PAI-1) gene were initially reported to be associated with an increased risk of osteonecrosis, 4,66 but this finding could not be confirmed by subsequent GWAS studies. 68 Osteonecrosis in children with ALL haematologica | 2016; 101(11) Likewise, findings about polymorphisms involved in lipid homeostasis (acid phosphatase locus 1, ACP1), 6 antifolate pharmacodynamics (thymidylate synthetase, TYMS), and steroid hormone response (vitamin D receptor, VDR), have been reported to be associated with osteonecrosis, 9 but were not reproducible in GWAS studies.…”

“…Mechanical load opens mechanosensitive calcium channels in osteocytes, leading to exocytosis of glutamate, which activates osteoblast receptors and impairs endothelial barrier function. [67][68][69][70] In addition, SNPs in adipogenesis pathways and in enhancers active in mesenchymal stem cells are significantly associated with osteonecrosis development. 67 Bone morphogenetic protein (BMP) is toxic to vascular smooth muscle and is released in response to bone damage and mechanical stress.…”

Osteonecrosis in children and adolescents with acute lymphoblastic leukemia: a therapeutic challenge

“…Notably, genetic data indicate that variants in MSCs may play a role in the development of osteonecrosis. 83 However, the immediate implications of this finding in therapy using autologous MSCs are unclear. As an alternative strategy, the use of banked cryopreserved allogeneic MSCs derived from healthy volunteer bone marrow donors may also be considered.…”

“…17,27,83 Although these studies have not directly translated into treatment strategies or identified robust predictors of ON, they have implicated various pathways (glutamate receptor pathway, adipogenesis pathways, enhancers active in MSCs, bone morphogenic protein) that could potentially be targeted in the future. However, one must keep in mind that the studies also demonstrated that genetic risk factors significantly depend on the patient's age.…”

Genetic Biomarkers to Identify the Risk of Osteonecrosis in Children with Acute Lymphoblastic Leukemia

“…Candidate single nucleotide polymorphisms (SNPs) in vitamin D receptor and thymidylate synthase genes [15], the plasminogen activator inhibitor PAI-1 gene [16], and the glutamate receptor GRIN3A gene [17] have been identified. The first genome-wide association study (GWAS) in children with ALL and osteonecrosis showed that rs75161997 in BMP7 and rs1891059 in PROX1-AS1 are associated with osteonecrosis [18]. These identified genes are important to bone and fat differentiation from mesenchymal stem cells.…”