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 (HR891TT = 2.4, 95% CI 1.2–4.8, P = 0.01 and HR29201CC = 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.
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Acknowledgements
We thank all patients and their parents who consented to participate in genetics studies related to leukemia. Leukemia Lymphoma Society of Canada, Canadian Institutes of Health Research and Charles Bruneau Foundation supported this study. Dana-Farber
Cancer Institute ALL treatment protocols are supported by the National Cancer Institute/NIH grant 5 P01CA06848
Author contributions
M.K. designed the study; M.P., V.G., M.Y. and B. S-A. performed experiments; M.P. and S.J-G performed medical chart reviews; C.L. JM.L., N.A, S.E.S., D.N. J.K, L.B.S and D.S. contributed to sample and clinical data collection and interpretation; M.P., V.G. and M.K. performed the data analysis; M.P. and M.K. drafted the article; All authors contributed to the interpretation of data and revised the manuscript.
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Plesa, M., Gagné, V., Glisovic, S. et al. Influence of BCL2L11 polymorphism on osteonecrosis during treatment of childhood acute lymphoblastic leukemia. Pharmacogenomics J 19, 33–41 (2019). https://doi.org/10.1038/s41397-017-0002-4
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DOI: https://doi.org/10.1038/s41397-017-0002-4