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:

Ikaros family zinc-finger 1 mutation is an independent factor for the poor prognosis of adult B-cell acute lymphoblastic leukemia, and allogeneic hematopoietic stem cell transplantation can improve clinical outcomes

Abstract

To investigate the prognosis of patients with adult B-cell acute lymphoblastic leukemia (B-ALL) with Ikaros family zinc-finger 1 (IKZF1) mutation and determine the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in improving the clinical outcome, we detected the IKZF1 mutation and BCR-ABL fusion gene at diagnosis in the bone marrow of 164 adult patients with B-ALL, and analyzed the clinical data of these patients retrospectively. Our analysis showed that grade III–IV acute graft-versus-host disease and IKZF1 mutation in the transplantation group and age and IKZF1 mutation in the non-transplantation group were independent factors for poor prognosis by univariate and multivariate analyses.The 3-year overall survival (OS) and leukemia-free survival (LFS) rates were much lower in the IKZF1+/BCR-ABL+ subgroup than in the IKZF1+/BCR-ABL− and IKZF1/BCR-ABL− subgroups in both the transplantation and non-transplantation groups. The 3-year OS and LFS rates were significantly higher in the transplantation group than in the non-transplantation group with IKZF1 mutation.The study demonstrated that IKZF1 mutation was an independent factor indicating the poor prognosis of adult B-ALL and much worse prognosis in the BCR-ABL+ subgroup in both non-transplantation and transplantation groups. However, allo-HSCT significantly improved the OS and LFS of patients and also their clinical outcomes.

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

Access options

Buy this article

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Paul S, Kantarjian H, Jabbour EJ. Adult acute lymphoblastic leukemia. Mayo Clin Proc. 2016;91:1645–66.

    Article  Google Scholar 

  2. Malagola M, Papayannidis C, Baccarani M. Tyrosine kinase inhibitors in Ph+ acute lymphoblastic leukaemia: facts and perspectives. Ann Hematol. 2016;95:681–93.

    Article  CAS  Google Scholar 

  3. Somasundaram R, Prasad MA, Unqerback J, Sigvardsson M. Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia. Blood. 2015;126:144–52.

    Article  CAS  Google Scholar 

  4. Yao L, Cen J, Chen S, Shen H, Chen Y, He J, et al. IK6 isoform with associated cytogenetic and molecular abnormalities in Chinese patients with Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Leuk Lymphoma. 2013;54:1626–32.

    Article  CAS  Google Scholar 

  5. Gupta SK, Bakhshi S, Kumar L, Seth R, Kumar R. IKZF1 (IKAROS) deletions in B-ALL and its clinical correlation: a prospective study from a tertiary care centre in Northern India. Leuk Res. 2016;41:7–11.

    Article  Google Scholar 

  6. Van der veer A, Zaliova M, Mottadelli F, De Lorenzo P, Te Kronnie G, Harrison CJ, et al. IKZF1 status as a prognostic feature in BCR-ABL1-positive childhood ALL. Blood. 2014;123:1691–8.

    Article  Google Scholar 

  7. Martinelli G, Lacobucci L, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D, et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report. J Clin Oncol. 2009;27:5202–7.

    Article  CAS  Google Scholar 

  8. Olsson L, Johansson B. Ikaros and leukaemia. Br J Haematol. 2015;169:479–91.

    Article  CAS  Google Scholar 

  9. Mullighan CG, Su X, Zhang J, Radtke L, Phillips LA, Miller GB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engi J Med. 2009;360:470–80.

    Article  CAS  Google Scholar 

  10. Kuiper RP, Waanders E, van der Velden VH, van Reijmersdal SV, Venkatachalam R, Scheijen B, et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia. 2010;24:1258–64.

    Article  CAS  Google Scholar 

  11. Clappier E, Grardel N, Bakkus M, Rapion J, De Moerloose B, Kastner P, et al. IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children’s Leukemia Group study 58951. Leukemia. 2015;29:2154–61.

    Article  CAS  Google Scholar 

  12. Wu X, He G, Fa Y, Ma X, Wu D, Ai H, et al. Comparable outcomes of partially matched related and matched related allogeneic hematopoietic cell transplantation following reduced-intensity conditioning in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia. Int J Hematol. 2013;98:456–62.

    Article  Google Scholar 

  13. Tian H, Xu Y, Liu L, Yan L, Jin Z, Tang X, et al. Comparison of outcomes in mixed phenotype acute leukemia patients treated with chemotherapy and stem cell transplantation versus chemotherapy alone. Leuk Res. 2016;45:40–6.

    Article  CAS  Google Scholar 

  14. Zhang YY, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. HLA-haploidentical hematopoietic SCT from collateral related donors without in vitro T-cell depletion for hematological malignancies. Bone Marrow Transplant. 2014;49:496–501.

    Article  Google Scholar 

  15. Marinescu C, Vlădăreanu AM, Mihai F. Acute lymphocytic leukemia in adults, pathologic features and prognosis. Rom J Intern Med. 2015;53:31–6.

    PubMed  Google Scholar 

  16. Ringden O, Pavletic SZ, Anasetti C, Barrett AJ, Wang T, Wang D, et al. The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoic stem cell transplantation. Blood. 2009;113:3110–8.

    Article  CAS  Google Scholar 

  17. Chiaretti S, Brugnoletti F, Tavolaro S, Bonina S, Paoloni F, Marinelli M, et al. TP53 mutations are frequent in adult acute lymphoblastic leukemia cases negative for recurrent fusion genes and correlate with poor response to induction therapy. Haematologica. 2013;98:e59–61.

    Article  Google Scholar 

  18. Wang Q, Qiu H, Jiang H, Wu L, Dong S, Pan J, et al. Mutations of PHF6 are associated with mutations of NOTCH1, JAK1 and rearrangement of SET-NUP214 in T-cell acute lymphoblastic leukemia. Haematologica. 2011;96:1808–14.

    Article  CAS  Google Scholar 

  19. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengliné E, et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a group for research in adult acute lymphoblastic leukemia study. J Clin Oncol. 2013;31:4333–42.

    Article  CAS  Google Scholar 

  20. Dorge 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;98:428–32.

    Article  Google Scholar 

  21. Asai D, Imamura T, Suenobu S, Saito A, Hasegawa D, Deguchi T, et al. IKZF1 deletion is associated with a poor outcome in pediatric B-cell precursor acute lymphoblastic leukemia in Japan. Cancer Med. 2013;2:412–9.

    Article  CAS  Google Scholar 

  22. Lacobucci I, Iraci N, Messina M, Lonetti A, Chiaretti S, Valli E, et al. IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia. PLoS ONE. 2012;7:e40934.

    Article  Google Scholar 

  23. Joshi I, Yoshida T, Jena N, Qi X, Zhang J, Van Etten RA, et al. Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia. Nat Immunol. 2014;15:294–304.

    Article  CAS  Google Scholar 

  24. Mullighan CG, Miller CB, Radtke L, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453:110–4.

    Article  CAS  Google Scholar 

  25. Schjerven H, Mclaughlin J, Arenzana TL, Frietze S, Cheng D, Wadsworth SE, et al. Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Nat Immunol. 2013;14:1073–83.

    Article  CAS  Google Scholar 

  26. Tonnelle C, Imbert MC, Sainty D, Granjeaud S, N’Guyen C, Chabannon C. Overexpression of dominant-negative Ikaros 6 protein is restricted to a subset of B common adult acute lymphoblastic leukemias that express high levels of the CD34 antigen. Hematol J. 2003;4:104–9.

    Article  CAS  Google Scholar 

  27. Theocharides AP, Dobson SM, Laurenti E, Notta F, Voisin V, Cheng PY, et al. Dominant-negative Ikaros cooperates with BCR- ABL1 to induce human acute myeloid leukemia in xenografts. Leukemia. 2015;29:177–87.

    Article  CAS  Google Scholar 

  28. Suzuki K, Ono R, Ohishi K, Masuya M, Kataoka I, Liu B, et al. IKAROS isoform 6 enhances BCR-ABL1-mediated proliferation of human CD34+ hematopoietic cells on stromal cells. Int J Oncol. 2012;40:53–62.

    CAS  PubMed  Google Scholar 

  29. Martinelli G, Lacobucci L, Storlazzi CT, Vignetti M, Paoloni F, Cilloni D, et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: a GIMEMA AL WP report. J Clin Oncol. 2009;27:5202–7.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by research grants from the National Key R&D Program of China (2016YFC0902800), the National Natural Science Foundation of China (81270645), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Frontier Clinical Technical Project of the Science and Technology Department of Jiangsu Province (BE2017655), and the Jiangsu Provincial Medical Talent (ZDRCA2016045).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Wu Depei or Tang Xiaowen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tang, S., Shen, H., Qu, C. et al. Ikaros family zinc-finger 1 mutation is an independent factor for the poor prognosis of adult B-cell acute lymphoblastic leukemia, and allogeneic hematopoietic stem cell transplantation can improve clinical outcomes. Bone Marrow Transplant 54, 236–243 (2019). https://doi.org/10.1038/s41409-018-0249-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0249-7

This article is cited by

Search

Quick links