Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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 (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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cumulative incidence of osteonecrosis in QcALL cohort in relationship to BCL2L11 polymorphisms 891T>G in a; and 29201C>T in b
Fig. 2: Frequency of BCL2L11 genotypes in relation to cellular viability and mRNA expression
Fig. 3: The frequency of 891 T>G BCL2L11 genotype in relation to osteonecrosis in replication cohort

Similar content being viewed by others

References

  1. Patel B, Richards SM, Rowe JM, Goldstone AH, Fielding AK. High incidence of avascular necrosis in adolescents with acute lymphoblastic leukaemia: a UKALL XII analysis. Leukemia 2008;22:308–12.

    Article  CAS  Google Scholar 

  2. Mattano LA Jr., Sather HN, Trigg ME, Nachman JB. Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 2000;18:3262–72.

    Article  Google Scholar 

  3. Arico M, Boccalatte MF, Silvestri D, Barisone E, Messina C, Chiesa R, et al Osteonecrosis: An emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia. Haematologica 2003;88:747–53.

    CAS  PubMed  Google Scholar 

  4. te Winkel ML, Appel IM, Pieters R, van den Heuvel-Eibrink MM. Impaired dexamethasone-related increase of anticoagulants is associated with the development of osteonecrosis in childhood acute lymphoblastic leukemia. Haematologica 2008;93:1570–4.

    Article  Google Scholar 

  5. Belgaumi AF, Al-Bakrah M, Al-Mahr M, Al-Jefri A, Al-Musa A, Saleh M, et al Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin. Cancer 2003;97:2898–903.

    Article  CAS  Google Scholar 

  6. Chan KL, Mok CC. Glucocorticoid-induced avascular bone necrosis: diagnosis and management. Open Othoped J 2012;6:449–57.

    Article  CAS  Google Scholar 

  7. Hyakuna N, Shimomura Y, Watanabe A, Taga T, Kikuta A, Matsushita T, et al Assessment of corticosteroid-induced osteonecrosis in children undergoing chemotherapy for acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer andLeukemia Study Group. J Pediatr Hematol Oncol 2014;36:22–29.

    Article  CAS  Google Scholar 

  8. Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB. Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 2001;19:3066–72.

    Article  CAS  Google Scholar 

  9. Silverman LB, Stevenson KE, O'Brien JE, Asselin BL, Barr RD, Clavell L, et al Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000). Leukemia 2010;24:320–34.

    Article  CAS  Google Scholar 

  10. Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell LA, et al Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001;97:1211–8.

    Article  CAS  Google Scholar 

  11. Moghrabi A, Levy DE, Asselin B, Barr R, Clavell L, Hurwitz C, et al Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 2007;109:896–904.

    Article  CAS  Google Scholar 

  12. Mazziotti G, Giustina A, Canalis E, Bilezikian JP. Glucocorticoid-induced osteoporosis: clinical and therapeutic aspects. Arq Bras Endocrinol Metabol 2007;51:1404–12.

    Article  Google Scholar 

  13. Alos N, Grant RM, Ramsay T, Halton J, Cummings EA, Miettunen PM, et al High incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy. J Clin Oncol 2012;30:2760–7.

    Article  CAS  Google Scholar 

  14. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 1998;102:274–82.

    Article  CAS  Google Scholar 

  15. Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 2006;126:789–99.

    Article  CAS  Google Scholar 

  16. Abu EO, Horner A, Kusec V, Triffitt JT, Compston JE. The localization of the functional glucocorticoid receptor alpha in human bone. J Clin Endocrinol Metab 2000;85:883–9.

    CAS  PubMed  Google Scholar 

  17. Biddie SC, Conway-Campbell BL, Lightman SL. Dynamic regulation of glucocorticoid signalling in health and disease. Rheumatology (Oxford) 2012;51:403–12.

    Article  CAS  Google Scholar 

  18. Huang DC, Strasser A. BH3-Only proteins-essential initiators of apoptotic cell death. Cell 2000;103:839–42.

    Article  CAS  Google Scholar 

  19. Webster JC, Cidlowski JA. Downregulation of the glucocorticoid receptor. A mechanism for physiological adaptation to hormones. Ann N Y Acad Sci 1994;746:216–20.

    Article  CAS  Google Scholar 

  20. Tonko M, Ausserlechner MJ, Bernhard D, Helmberg A, Kofler R. Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis. FASEB J 2001;15:693–9.

    Article  CAS  Google Scholar 

  21. Liu C, Janke LJ, Kawedia JD, Ramsey LB, Cai X, Mattano LA Jr, et al Asparaginase potentiates glucocorticoid-induced osteonecrosis in a mouse model. PLoS ONE 2016;11:e0151433.

    Article  Google Scholar 

  22. Niinimaki RA, Harila-Saari AH, Jartti AE, Seuri RM, Riikonen PV, Paakko EL, et al High body mass index increases the risk for osteonecrosis in children with acute lymphoblastic leukemia. J Clin Oncol 2007;25:1498–504.

    Article  Google Scholar 

  23. Bernbeck B, Mauz-Korholz C, Zotz RB, Gobel U. Methylenetetrahydrofolate reductase gene polymorphism and glucocorticoid intake in children with ALL and aseptic osteonecrosis. Klin Padiatr 2003;215:327–31.

    Article  CAS  Google Scholar 

  24. Karol SE, Mattano LA Jr., Yang W, Maloney KW, Smith C, Liu C, et al Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. Blood 2016;127:558–64.

    Article  CAS  Google Scholar 

  25. Karol SE, Yang W, Van Driest SL, Chang TY, Kaste S, Bowton E, et al Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Blood 2015;126:1770–6.

    Article  CAS  Google Scholar 

  26. Kawedia JD, Kaste SC, Pei D, Panetta JC, Cai X, Cheng C, et al Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood 2011;117:2340–7. quiz 2556

    Article  CAS  Google Scholar 

  27. French D, Hamilton LH, Mattano LA Jr, Sather HN, Devidas M, Nachman JB, et al A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 2008;111:4496–9.

    Article  CAS  Google Scholar 

  28. Medh RD, Webb MS, Miller AL, Johnson BH, Fofanov Y, Li T, et al Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics 2003;81:543–55.

    Article  CAS  Google Scholar 

  29. O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, et al Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 1998;17:384–95.

    Article  CAS  Google Scholar 

  30. Iglesias-Serret D, de Frias M, Santidrian AF, Coll-Mulet L, Cosialls AM, Barragan M, et al Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells. Leukemia 2007;21:281–7.

    Article  CAS  Google Scholar 

  31. Espina B, Liang M, Russell RG, Hulley PA. Regulation of bim in glucocorticoid-mediated osteoblast apoptosis. J Cell Physiol 2008;215:488–96.

    Article  CAS  Google Scholar 

  32. Gagne V, Rousseau J, Labuda M, Sharif-Askari B, Brukner I, Laverdiere C, et al Bim polymorphisms: influence on function and response to treatment in children with acute lymphoblastic leukemia. Clin Cancer Res 2013;19:5240–9.

    Article  CAS  Google Scholar 

  33. Vrooman LM, Stevenson KE, Supko JG, O'Brien J, Dahlberg SE, Asselin BL, et al Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 2013;31:1202–10.

    Article  CAS  Google Scholar 

  34. DCTD NCI (2006). National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.

  35. Labuda D, Krajinovic M, Richer C, Skoll A, Sinnett H, Yotova V, et al Rapid detection of CYP1A1, CYP2D6, and NAT variants by multiplex polymerase chain reaction and allele-specific oligonucleotide assay. Anal Biochem 1999;275:84–92.

    Article  CAS  Google Scholar 

  36. Storey JDTJ, Siegmund D. . Strong control, conservative point estimation and simultaneous conservative consistency of false discovery rates: a unified approach. J R Stat Soc 2004;66:187–205.

    Article  Google Scholar 

  37. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif) 2001;25:402–8.

    Article  CAS  Google Scholar 

  38. Anczukow O, Rosenberg AZ, Akerman M, Das S, Zhan L, Karni R, et al The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol 2012;19:220–8.

    Article  CAS  Google Scholar 

  39. Kelly JL, Novak AJ, Fredericksen ZS, Liebow M, Ansell SM, Dogan A, et al Germline variation in apoptosis pathway genes and risk of non-Hodgkin's lymphoma. Cancer Epidemiol Biomark Prevent 2010;19:2847–58.

    Article  CAS  Google Scholar 

  40. Miao J, Chen GG, Yun JP, Chun SY, Zheng ZZ, Ho RL, et al Identification and characterization of BH3 domain protein Bim and its isoforms in human hepatocellular carcinomas. Apoptosis 2007;12:1691–701.

    Article  CAS  Google Scholar 

  41. Mattano LA Jr, Devidas M, Nachman JB, Sather HN, Hunger SP, Steinherz PG, et al Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol 2012;13:906–15.

    Article  CAS  Google Scholar 

  42. Sato M, Sugano N, Ohzono K, Nomura S, Kitamura Y, Tsukamoto Y, et al Apoptosis and expression of stress protein (ORP150, HO1) during development of ischaemic osteonecrosis in the rat. J Bone Joint Surg Br 2001;83:751–9.

    Article  CAS  Google Scholar 

  43. Zalavras C, Shah S, Birnbaum MJ, Frenkel B. Role of apoptosis in glucocorticoid-induced osteoporosis and osteonecrosis. Crit Rev Eukaryot Gene Expr 2003;13:221–35.

    Article  CAS  Google Scholar 

  44. Kabata T, Kubo T, Matsumoto T, Nishino M, Tomita K, Katsuda S, et al Apoptotic cell death in steroid induced osteonecrosis: an experimental study in rabbits. J Rheumatol 2000;27:2166–71.

    CAS  PubMed  Google Scholar 

  45. Nott A, Meislin SH, Moore MJ. A quantitative analysis of intron effects on mammalian gene expression. RNA (New York, NY) 2003;9:607–17.

    Article  CAS  Google Scholar 

  46. Ge W, Shi L, Zhou Y, Liu Y, Ma GE, Jiang Y, et al Inhibition of osteogenic differentiation of human adipose-derived stromal cells by retinoblastoma binding protein 2 repression of RUNX2-activated transcription. Stem Cells 2011;29:1112–25.

    Article  CAS  Google Scholar 

  47. Heidari N, Miller AV, Hicks MA, Marking CB, Harada H. Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c-Jun in leukemia cells. Cell Death Dis 2012;3:e349.

    Article  CAS  Google Scholar 

  48. Bachmann PS, Gorman R, Papa RA, Bardell JE, Ford J, Kees UR, et al Divergent mechanisms of glucocorticoid resistance in experimental models of pediatric acute lymphoblastic leukemia. Cancer Res 2007;67:4482–90.

    Article  CAS  Google Scholar 

  49. Bachmann PS, Gorman R, Mackenzie KL, Lutze-Mann L, Lock RB. Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor. Blood 2005;105:2519–26.

    Article  CAS  Google Scholar 

  50. Wang Z, Malone MH, He H, McColl KS, Distelhorst CW. Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis. J Biol Chem 2003;278:23861–7.

    Article  CAS  Google Scholar 

  51. Hunt R, Sauna ZE, Ambudkar SV, Gottesman MM, Kimchi-Sarfaty C. Silent (synonymous) SNPs: should we care about them? Methods Mol Biol 2009;578:23–39.

    Article  CAS  Google Scholar 

  52. Augis V, Airiau K, Josselin M, Turcq B, Mahon FX, Belloc F. A single nucleotide polymorphism in cBIM is associated with a slower achievement of major molecular response in chronic myeloid leukaemia treated with imatinib. PLoS ONE 2013;8:e78582.

    Article  CAS  Google Scholar 

  53. Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK, Teo AS, et al A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 2012;18:521–8.

    Article  CAS  Google Scholar 

  54. Katagiri STT, Tadokoro K, Ohyashiki JH, Ohyashiki K. BCL2L11 (BIM) deletion polymorphism, rather than BIM SNP, is an effective predictor of early molecular relapse after ABL tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia. Integr Cancer Sci Therap 2015;2:242–4.

    Google Scholar 

  55. Lee JH, Lin YL, Hsu WH, Chen HY, Chang YC, Yu CJ, et al Bcl-2-like protein 11 deletion polymorphism predicts survival in advanced non-small-cell lung cancer. J Thorac Oncol 2014;9:1385–92.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maja Krajinovic.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-017-0002-4

Search

Quick links