Abstract
Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4–7 and exons 1–8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case–control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2–7 (P=0.03), DEL 2–8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4–7 and DEL 1–8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pui CH, Evans WE . Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–178.
Moricke A, Zimmermann M, Reiter A, Henze G, Schrauder A, Gadner H et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia 2010; 24: 265–284.
Waanders E, van der Velden VH, van der Schoot CE, van Leeuwen FN, van Reijmersdal SV, de Haas V et al. Integrated use of minimal residual disease classification and IKZF1 alteration status accurately predicts 79% of relapses in pediatric acute lymphoblastic leukemia. Leukemia 2011; 25: 254–258.
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.
Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009; 360: 470–480.
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: 1258–1264.
Dorge P, Meissner B, Zimmermann M, Moricke 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.
Yang YL, Hung CC, Chen JS, Lin KH, Jou ST, Hsiao CC et al. IKZF1 deletions predict a poor prognosis in children with B-cell progenitor acute lymphoblastic leukemia: a multicenter analysis in Taiwan. Cancer Sci 2011; 102: 1874–1881.
Volejnikova J, Mejstrikova E, Dorge P, Meissner B, Zimmermannova O, Svojgr K et al. Ikaros (IKZF1) alterations and minimal residual disease at day 15 assessed by flow cytometry predict prognosis of childhood BCR/ABL-negative acute lymphoblastic leukemia. Pediatr Blood Cancer 2013; 60: 420–427.
Olsson L, Ivanov Ofverholm I, Noren-Nystrom U, Zachariadis V, Nordlund J, Sjogren H et al. The clinical impact of IKZF1 deletions in paediatric B-cell precursor acute lymphoblastic leukaemia is independent of minimal residual disease stratification in Nordic Society for Paediatric Haematology and Oncology treatment protocols used between 1992 and 2013. Br J Haematol 2015; e-pub ahead of print 27 May 2015; doi:10.1111/bjh.13514.
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; e-pub ahead of print 8 June 2015; doi:10.1038/leu.2015.134.
Kaufmann C, Yoshida T, Perotti EA, Landhuis E, Wu P, Georgopoulos K . A complex network of regulatory elements in Ikaros and their activity during hemo-lymphopoiesis. EMBO J 2003; 22: 2211–2223.
Georgopoulos K, Bigby M, Wang JH, Molnar A, Wu P, Winandy S et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 1994; 79: 143–156.
Yoshida T, Landhuis E, Dose M, Hazan I, Zhang J, Naito T et al. Transcriptional regulation of the Ikzf1 locus. Blood 2013; 122: 3149–3159.
Yoshida T, Georgopoulos K . Ikaros fingers on lymphocyte differentiation. Int J Hematol 2014; 100: 220–229.
Ferreiros-Vidal I, Carroll T, Taylor B, Terry A, Liang Z, Bruno L et al. Genome-wide identification of Ikaros targets elucidates its contribution to mouse B-cell lineage specification and pre-B-cell differentiation. Blood 2013; 121: 1769–1782.
Sun L, Liu A, Georgopoulos K . Zinc finger-mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. EMBO J 1996; 15: 5358–5369.
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: 1073–1083.
Bottardi S, Mavoungou L, Bourgoin V, Mashtalir N, Affar el B, Milot E . Direct protein interactions are responsible for Ikaros-GATA and Ikaros-Cdk9 cooperativeness in hematopoietic cells. Mol Cell Biol 2013; 33: 3064–3076.
Tokunaga K, Yamaguchi S, Iwanaga E, Nanri T, Shimomura T, Suzushima H et al. High frequency of IKZF1 genetic alterations in adult patients with B-cell acute lymphoblastic leukemia. Eur J Haematol 2013; 91: 201–208.
Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 2008; 453: 110–114.
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: 1691–1698.
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.
Sun L, Heerema N, Crotty L, Wu X, Navara C, Vassilev A et al. Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. Proc Natl Acad Sci USA 1999; 96: 680–685.
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.
Nishii K, Katayama N, Miwa H, Shikami M, Usui E, Masuya M et al. Non-DNA-binding Ikaros isoform gene expressed in adult B-precursor acute lymphoblastic leukemia. Leukemia 2002; 16: 1285–1292.
Klein F, Feldhahn N, Herzog S, Sprangers M, Mooster JL, Jumaa H et al. BCR-ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells. Oncogene 2006; 25: 1118–1124.
Dupuis A, Gaub MP, Legrain M, Drenou B, Mauvieux L, Lutz P et al. Biclonal and biallelic deletions occur in 20% of B-ALL cases with IKZF1 mutations. Leukemia 2013; 27: 503–507.
Caye A, Beldjord K, Mass-Malo K, Drunat S, Soulier J, Gandemer V et al. Breakpoint-specific multiplex polymerase chain reaction allows the detection of IKZF1 intragenic deletions and minimal residual disease monitoring in B-cell precursor acute lymphoblastic leukemia. Haematologica 2013; 98: 597–601.
Palmi C, Lana T, Silvestri D, Savino A, Kronnie GT, Conter V et al. Impact of IKZF1 deletions on IKZF1 expression and outcome in Philadelphia chromosome negative childhood BCP-ALL. Reply to "Incidence and biological significance of IKZF1/Ikaros gene deletions in pediatric Philadelphia chromosome negative and Philadelphia chromosome positive B-cell precursor acute lymphoblastic leukemia". Haematologica 2013; 98: e164–e165.
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.
Therneau T, Grambsch P . Modeling Survival Data: Extending the Cox Model. Springer-Verlag: New York, chapter 8: 2000.
Schwickert TA, Tagoh H, Gultekin S, Dakic A, Axelsson E, Minnich M et al. Stage-specific control of early B cell development by the transcription factor Ikaros. Nat Immunol 2014; 15: 283–293.
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.
Enshaei A, Schwab CJ, Konn ZJ, Mitchell CD, Kinsey SE, Wade R et al. Long-term follow-up of ETV6-RUNX1 ALL reveals that NCI risk, rather than secondary genetic abnormalities, is the key risk factor. Leukemia 2013; 27: 2256–2259.
Clappier E, Auclerc MF, Rapion J, Bakkus M, Caye A, Khemiri A et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia 2014; 28: 70–77.
Zaliova M, Zimmermannova O, Dorge P, Eckert C, Moricke A, Zimmermann M et al. ERG deletion is associated with CD2 and attenuates the negative impact of IKZF1 deletion in childhood acute lymphoblastic leukemia. Leukemia 2014; 28: 182–185.
Payne KJ, Nicolas J-H, Zhu JY, Barsky LW, Crooks GM . Cutting edge: predominant expression of a novel Ikaros isoform in normal human hemopoiesis. J Immunol 2001; 167: 1867–1870.
Iacobucci I, Storlazzi CT, Cilloni D, Lonetti A, Ottaviani E, Soverini S et al. Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell'Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood 2009; 114: 2159–2167.
Papaemmanuil E, Rapado I, Li Y, Potter NE, Wedge DC, Tubio J et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet 2014; 46: 116–125.
Olsson L, Albitar F, Castor A, Behrendtz M, Biloglav A, Paulsson K et al. Cooperative genetic changes in pediatric B-cell precursor acute lymphoblastic leukemia with deletions or mutations of IKZF1. Genes Chromosomes Cancer 2015; 54: 315–325.
Marshall GM, Dalla Pozza L, Sutton R, Ng A, de Groot-Kruseman HA, van der Velden VH et al. High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation. Leukemia 2013; 27: 1497–1503.
Churchman M, Low J, Payne-Turner D, Chen S-C, Ma J, Althoff MJ et al. High content screening identifies synthetic lethality of retinoid receptor agonists in IKZF1-mutated BCR-ABL1 positive acute lymphoblastic leukemia. Blood 2013; 122: 172.
Papathanasiou P, Attema JL, Karsunky H, Hosen N, Sontani Y, Hoyne GF et al. Self-renewal of the long-term reconstituting subset of hematopoietic stem cells is regulated by Ikaros. Stem Cells 2009; 27: 3082–3092.
Acknowledgements
This work was supported by the Dutch Cancer Society (KWF, Grant EMCR 2007-3718 to MLdB and RP; Grant KUN 2009-4298 to RPK and PH), the Sophia Foundation for Scientific Research (SSWO, grant 658 to AvdV and MLdB), the Paediatric Oncology Foundation Rotterdam (to MLdB and RP), the European Union’s Seventh Framework Program (FP7/2007-2013) under the project European Network for Cancer research in Children and Adolescents (ENCCA, grant agreement HEALTH-F2-2011-261474 to MLdB and GC), the Center for Translational Molecular Medicine BioChip program (to MLdB), the National Health and Medical Research Council and Tour de Cure Foundation in Australia (to RS), the Polish Ministry of Education and Science (project NN407 137738 and project NN407 254440 to WM), the Polpharma Scientific Foundation (to WM), Anniversary of the Austrian National Bank (ÖNB, Grant 14133 to KN), Italian Association for Cancer Research (AIRC), the Czech Ministry of Health (NT 12397-4 to EF; NT 13170-4 to MZa) and Fondazione Cariplo and MIUR (to GC). AVM, CJS, AE and AV thank Leukaemia & Lymphoma Research (LLR) for financial support and the UK Cancer Cytogenetic Group (UKCCG) laboratories and the LLR Childhood Leukaemia Cell Bank for providing data and samples.
Author contributions
MLdB, AvdV, MZi, AVM and RP designed this study. Patients’ samples and follow-up data were supplied by HAdGK, PH, JT, MH, MdSPdO, WM, AA, RS, AE, MSc, AV, GC, VC, MZi and AVM. Multiplex ligation-dependent probe amplification assays were performed by AvdV, ES, RPK, MZa, EF, ME, TS, KN, AA, NV, CJS, MSt and CP. AvdV, JMB, DR, MF, HAdGK, MZi, AVM and MLdB performed the statistical analysis of data. The manuscript was written and approved by all authors.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Leukemia website
Rights and permissions
About this article
Cite this article
Boer, J., van der Veer, A., Rizopoulos, D. et al. Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study. Leukemia 30, 32–38 (2016). https://doi.org/10.1038/leu.2015.199
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2015.199
This article is cited by
-
‘Evaluation of adverse prognostic gene alterations & MRD positivity in BCR::ABL1-like B-lineage acute lymphoblastic leukaemia patients, in a resource-constrained setting
British Journal of Cancer (2023)
-
Prevalence and prognostic significance of IKZF1 deletion in paediatric acute lymphoblastic leukemia: A systematic review and meta-analysis
Annals of Hematology (2023)
-
The recombinome of IKZF1 deletions in B-cell precursor ALL
Leukemia (2023)
-
Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia
Leukemia (2023)
-
Dominant-negative type of IKZF1 deletion showed a favorable prognosis in adult B-cell acute lymphoblastic leukemia
Annals of Hematology (2023)