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Prognostic significance of cytokine receptor-like factor 2 alterations in acute lymphoblastic leukemia: a meta-analysis

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Abstract

Background

Cytokine receptor-like factor 2 (CRLF2) has been shown to play a role in the pathogenesis of acute lymphoblastic leukemia (ALL). Studies have examined the relationship between CRLF2 alterations such as over-expression or deregulation and clinical outcome in childhood ALL, but the results are conflicting. This meta-analysis aimed to explore the association between CRLF2 alterations and survival of pediatric patients with ALL.

Methods

Electronic databases updated to March 2014 were searched for relevant studies. A meta-analysis was made of twelve studies including 5945 patients to evaluate the prognostic significance of CRLF2 alterations on survival in childhood ALL. Hazards ratios (HRs) with 95% confidence intervals (CIs) were pooled across the studies using a fixed-effects model.

Results

CRLF2 over-expression in childhood ALL was associated with poor prognosis in terms of relapse-free survival (RFS; HR=1.70, 95% CI=1.28–2.24, P=0.000), event-free survival (EFS; HR=1.78, 95% CI=1.05–3.01, P=0.032), and overall survival (OS; HR=2.28, 95% CI=1.42–3.65, P=0.001). The combined data also suggested that CRLF2 deregulation in childhood ALL was correlated with poor EFS (HR=1.95, 95% CI=1.46–2.61, P=0.000), RFS (HR=2.20, 95% CI=1.53–3.18, P=0.000), and OS (HR=1.89, 95% CI=1.24–2.87, P=0.003). Subgroup analysis on multivariate HRs showed that CRLF2 deregulation independently predicted a poor prognosis for childhood ALL.

Conclusions

The present meta-analysis reveals that both CRLF2 over-expression and deregulation are associated with poor prognosis in pediatric patients with ALL.

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References

  1. van der Veer A, Waanders E, Pieters R, Willemse ME, Van Reijmersdal SV, Russell LJ, et al. Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL. Blood 2013;122:2622–2629.

    Article  PubMed Central  PubMed  Google Scholar 

  2. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. Leukemia 2000;14:2205–2222.

    Article  CAS  PubMed  Google Scholar 

  3. Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2008;111:4477–4489.

    Article  PubMed  Google Scholar 

  4. Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ, et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. Blood 2009;114:2688–2698.

    Article  CAS  PubMed  Google Scholar 

  5. Mullighan CG, Collins-Underwood JR, Phillips LA, Loudin MG, Liu W, Zhang J, et al. Rearrangement of CRLF2 in B-progenitorand Down syndrome-associated acute lymphoblastic leukemia. Nat Genet 2009;41:1243–1246.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Hertzberg L, Vendramini E, Ganmore I, Cazzaniga G, Schmitz M, Chalker J, et al. Down syndrome acute lymphoblastic leukemia, a highly heterogeneous disease in which aberrant expression of CRLF2 is associated with mutated JAK2: a report from the International BFM Study Group. Blood 2010;115:1006–1017.

    Article  CAS  PubMed  Google Scholar 

  7. Chen IM, Harvey RC, Mullighan CG, Gastier-Foster J, Wharton W, Kang H, et al. Outcome modeling with CRLF2, IKZF1, JAK, and minimal residual disease in pediatric acute lymphoblastic leukemia: a Children’s Oncology Group study. Blood 2012;119:3512–3522.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Mi JQ, Wang X, Yao Y, Lu HJ, Jiang XX, Zhou JF, et al. Newly diagnosed acute lymphoblastic leukemia in China (II): prognosis related to genetic abnormalities in a series of 1091 cases. Leukemia 2012;26:1507–1516.

    Article  CAS  PubMed  Google Scholar 

  9. Cario G, Zimmermann M, Romey R, Gesk S, Vater I, Harbott J, et al. Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol. Blood 2010;115:5393–5397.

    Article  CAS  PubMed  Google Scholar 

  10. Palmi C, Vendramini E, Silvestri D, Longinotti G, Frison D, Cario G, et al. Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia. Leukemia 2012;26:2245–2253.

    Article  CAS  PubMed  Google Scholar 

  11. Yamashita Y, Shimada A, Yamada T, Yamaji K, Hori T, Tsurusawa M, et al. IKZF1 and CRLF2 gene alterations correlate with poor prognosis in Japanese BCR-ABL1-negative high-risk B-cell precursor acute lymphoblastic leukemia. Pediatr Blood Cancer 2013;60:1587–1592.

    Article  CAS  PubMed  Google Scholar 

  12. Ensor HM, Schwab C, Russell LJ, Richards SM, Morrison H, Masic D, et al. Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial. Blood 2011;117:2129–2136.

    Article  CAS  PubMed  Google Scholar 

  13. Morak M, Attarbaschi A, Fischer S, Nassimbeni C, Grausenburger R, Bastelberger S, et al. Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL. Blood 2012;120:5134–5142.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Palmi C, Valsecchi MG, Longinotti G, Silvestri D, Carrino V, Conter V, et al. What is the relevance of Ikaros gene deletions as a prognostic marker in pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia? Haematologica 2013;98:1226–1231.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Dörge P, Meissner B, Zimmermann M, Möricke A, Schrauder A, Bouquin JP, et al. IKZF1 deletion is an independent predictor of outcome in pediatric acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica 2013;98:428–432.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Buitenkamp TD, Pieters R, Gallimore NE, van der Veer A, Meijerink JP, Beverloo HB, et al. Outcome in children with Down’s syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations. Leukemia 2012;26:2204–2211.

    Article  CAS  PubMed  Google Scholar 

  17. Haslam K, Kelly J, Morris T, Connaghan G, Gilligan O, Browne P, et al. Screening for CRLF2 overexpression in adult acute lymphoblastic leukemia. Int J Lab Hematol 2011;33:e17–e19.

    Article  CAS  PubMed  Google Scholar 

  18. Altman DG. Systematic reviews of evaluations of prognostic variables. BMJ 2001;323:224–228.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335–371.

    Article  CAS  PubMed  Google Scholar 

  21. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–1101.

    Article  CAS  PubMed  Google Scholar 

  22. Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315:629–634.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Pui CH, Behm FG, Downing JR, Hancock ML, Shurtleff SA, Ribeiro RC, et al. 11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. J Clin Oncol 1994;12:909–915.

    CAS  PubMed  Google Scholar 

  24. Pui CH, Pei D, Sandlund JT, Campana D, Ribeiro RC, Razzouk BI, et al. Risk of adverse events after completion of therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 2005;23:7936–7941.

    Article  PubMed  Google Scholar 

  25. Teitell MA, Pandolfi PP. Molecular genetics of acute lymphoblastic leukemia. Annu Rev Pathol 2009;4:175–198.

    Article  CAS  PubMed  Google Scholar 

  26. Uckun FM, Nachman JB, Sather HN, Sensel MG, Kraft P, Steinherz PG, et al. Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies: a report from the Children’s Cancer Group. Cancer 1998;83:2030–2039.

    Article  CAS  PubMed  Google Scholar 

  27. Forestier E, Izraeli S, Beverloo B, Haas O, Pession A, Michalova K, et al. Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFMSG study. Blood 2008;111:1575–1583.

    Article  CAS  PubMed  Google Scholar 

  28. Attarbaschi A, Morak M, Cario G, Cazzaniga G, Ensor HM, te Kronnie T, et al. Treatment outcome of CRLF2-rearranged childhood acute lymphoblastic leukaemia: a comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups. Br J Haematol 2012;158:772–777.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Yong-Min Tang.

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Jia, M., Wang, ZJ., Zhao, HZ. et al. Prognostic significance of cytokine receptor-like factor 2 alterations in acute lymphoblastic leukemia: a meta-analysis. World J Pediatr 11, 126–133 (2015). https://doi.org/10.1007/s12519-015-0019-1

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  • DOI: https://doi.org/10.1007/s12519-015-0019-1

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