Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia

Abstract

Osteonecrosis (ON) is corticosteroid-related complication, reported in children with acute lymphoblastic leukemia (ALL). We have previously found that polymorphisms in BCL2L11 gene coding for pro-apoptotic Bim protein influence reduction of overall survival (OS) in a corticosteroid (CS) dose-dependent manner in childhood ALL patients. The same set of SNPs was here investigated for an association with CS-related ON assessed retrospectively in 304 children with ALL from Quebec (QcALL cohort) who received Dana-Farber Cancer Institute (DFCI) ALL treatment protocols. Two-year cumulative incidence of symptomatic ON was 10.6%. Two BCL2L11 polymorphisms, the 891T>G (rs2241843) in all QcALL patients and 29201C>T (rs724710) in high-risk group were significantly associated with ON, P = 0.009 and P = 0.003, respectively. The association remained significant in multivariate model (HR = 2.4, 95% CI 1.2-4.8, P = 0.01 and HR = 5.7, 95% CI 1.6-20.9, P = 0.008). Both polymorphisms influenced viability of dexamethasone treated lymphoblastoid cell lines (P ≤ 0.03). The 891T>G influenced Bim gamma isoform levels (0.03) and its association with ON was also confirmed in replication DFCI cohort (N = 168, P = 0.03). QcALL children had a high incidence of ON during therapy, which was highly associated with BCL2L11 polymorphisms.

Genetic polymorphism of vitamin D receptors and plasminogen activator inhibitor‐1 and osteonecrosis risk in childhood acute lymphoblastic leukemia

“…Padhye et al, ( 2016 ) and Sakamoto et al, ( 2018 ) reported that the incidence of ON is 7% among their study population. Moreover, Mattano et al, ( 2000 ), Plesa et al, ( 2019 ), and Pui et al, ( 2009 ), reported that the prevalence of ON among their patients was 9.3%, 10.5%, and 12%, respectively. The published prevalence of ON in children with ALL varies widely depending on the definition of ON, treatment protocol, and selection of patients.…”

“…Another risk factor for ON is sex. Many studies reported higher risk of ON in girls than boys (Aricò et al, 2003; French et al, 2008; Högler et al, 2007; Plesa et al, 2019; Strauss et al, 2001; Te Winkel et al., 2011), which was found in our study although other studies have not confirmed this (Barr & Sala, 2008; Mory et al, 2009).…”

Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials

“…Table 2 shows the 5-year CI of orthopedic events for patient subgroups. The majority of the 100 ON events documented occurred in the hip (48) with the remainder occurring in the knee (20) and other locations (32).…”

Pharmacogenomics as a Tool to Limit Acute and Long-Term Adverse Effects of Chemotherapeutics: An Update in Pediatric Oncology

“…The 891T>G was also confirmed in a replication cohort and influenced in vitro Bim gamma isoform levels. Bim proteins are believed to be involved in the sensitivity of ALL cells to corticosteroid-induced apoptosis ( Plesa et al., 2019 ). A GWAS in children with ALL and osteonecrosis showed that the SNP rs10989692 near the glutamate receptor GRIN3A locus, was associated with osteonecrosis ( Karol et al., 2015 ).…”