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  • Original Article
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Acute Leukemias

CREBBP HAT domain mutations prevail in relapse cases of high hyperdiploid childhood acute lymphoblastic leukemia

Leukemia volume 26, pages 1797–1803 (2012)Cite this article

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Abstract

Despite their apparently good prognosis ∼15% of high hyperdiploid (HD) childhood acute lymphoblastic leukemia (ALL) cases relapse. To search for responsible risk factors we determined copy number aberrations as well as copy neutral loss of heterozygosity (LOH) in 13 matched diagnosis and relapse samples and added the data of the only three available cases from the literature. Deletions and copy neutral LOH in 3 and 2 of the 16 cases directed us to the histone-modifying CREB-binding protein (CREBBP) gene, whose functional impairment is implicated in drug resistance. We therefore screened all samples for mutations in this gene and discovered 9 acquired sequence mutations in 7/16 cases, leading to an overall frequency of somatic CREBBP aberrations in HD ALL relapse cases of 63% that is considerably higher than that of the reported, mainly non-HD ALL (18.3%). Moreover, mutations in HD cases occur almost exclusively in the HAT domain (8/9; 89%). Hot spot mutations are present at diagnosis in 18.8% of relapsing HD ALL cases but in none of 40 respective cases remaining in long-term remission. Thus, the particular high incidence of CREBBP mutations in relapse-prone HD ALL cases could eventually be exploited for refined risk stratification and customized treatment in this genetic subgroup.

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References

  1. Paulsson K, Johansson B . High hyperdiploid childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer 2009; 48: 637–660.

    Article  CAS  Google Scholar 

  2. Pui CH, Robison LL, Look AT . Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030–1043.

    Article  CAS  Google Scholar 

  3. Greaves MF, Wiemels J . Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer 2003; 3: 639–649.

    Article  CAS  Google Scholar 

  4. Maia AT, van der Velden VH, Harrison CJ, Szczepanski T, Williams MD, Griffiths MJ et al. Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins. Leukemia 2003; 17: 2202–2206.

    Article  CAS  Google Scholar 

  5. Panzer-Grumayer ER, Fasching K, Panzer S, Hettinger K, Schmitt K, Stockler-Ipsiroglu S et al. Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis. Blood 2002; 100: 347–349.

    Article  CAS  Google Scholar 

  6. Paulsson K, Forestier E, Lilljebjorn H, Heldrup J, Behrendtz M, Young BD et al. Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA 2010; 107: 21719–21724.

    Article  CAS  Google Scholar 

  7. Moorman AV, Ensor HM, Richards SM, Chilton L, Schwab C, Kinsey SE et al. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol 2010; 11: 429–438.

    Article  CAS  Google Scholar 

  8. Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol 2010; 28: 2339–2347.

    Article  CAS  Google Scholar 

  9. Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood 2010; 115: 3206–3214.

    Article  CAS  Google Scholar 

  10. Davidsson J, Paulsson K, Lindgren D, Lilljebjorn H, Chaplin T, Forestier E et al. Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations. Leukemia 2010; 24: 924–931.

    Article  CAS  Google Scholar 

  11. Kawamata N, Ogawa S, Seeger K, Kirschner-Schwabe R, Huynh T, Chen J et al. Molecular allelokaryotyping of relapsed pediatric acute lymphoblastic leukemia. Int J Oncol 2009; 34: 1603–1612.

    Article  CAS  Google Scholar 

  12. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322: 1377–1380.

    Article  CAS  Google Scholar 

  13. Roelfsema JH, Peters DJ . Rubinstein-Taybi syndrome: clinical and molecular overview. Expert Rev Mol Med 2007; 9: 1–16.

    Article  Google Scholar 

  14. Zhang J, Mullighan CG, Harvey RC, Wu G, Chen X, Edmonson M et al. Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 2011; 118: 3080–3087.

    Article  CAS  Google Scholar 

  15. Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 2011; 471: 235–239.

    Article  CAS  Google Scholar 

  16. Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 2011; 471: 189–195.

    Article  CAS  Google Scholar 

  17. Flohr T, Schrauder A, Cazzaniga G, Panzer-Grumayer R, van der Velden V, Fischer S et al. Minimal residual disease-directed risk stratification using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000 for childhood acute lymphoblastic leukemia. Leukemia 2008; 22: 771–782.

    Article  CAS  Google Scholar 

  18. Kuster L, Grausenburger R, Fuka G, Kaindl U, Krapf G, Inthal A et al. ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling. Blood 2011; 117: 2658–2667.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. Talamo A, Chalandon Y, Marazzi A, Jotterand M . Clonal heterogeneity and chromosomal instability at disease presentation in high hyperdiploid acute lymphoblastic leukemia. Cancer Genet Cytogenet 2010; 203: 209–214.

    Article  CAS  Google Scholar 

  21. Kawamata N, Ogawa S, Zimmermann M, Kato M, Sanada M, Hemminki K et al. Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood 2008; 111: 776–784.

    Article  CAS  Google Scholar 

  22. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758–764.

    Article  CAS  Google Scholar 

  23. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011; 333: 1157–1160.

    Article  CAS  Google Scholar 

  24. van der Velden VH, Panzer-Grumayer ER, Cazzaniga G, Flohr T, Sutton R, Schrauder A et al. Optimization of PCR-based minimal residual disease diagnostics for childhood acute lymphoblastic leukemia in a multi-center setting. Leukemia 2007; 21: 706–713.

    Article  CAS  Google Scholar 

  25. Eckert C, Biondi A, Seeger K, Cazzaniga G, Hartmann R, Beyermann B et al. Prognostic value of minimal residual disease in relapsed childhood acute lymphoblastic leukaemia. Lancet 2001; 358: 1239–1241.

    Article  CAS  Google Scholar 

  26. Kuiper RP, Schoenmakers EF, van Reijmersdal SV, Hehir-Kwa JY, van Kessel AG, van Leeuwen FN et al. High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 2007; 21: 1258–1266.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the patients and their parents as well as physicians involved in this study, Andishe Attarbaschi for providing clinical data and Marion Zavadil for proofreading. This study is supported in part by Grants from the Austrian National Bank (ÖNB 12519 and 13881) to GM, Grant P18046-B12 of the Austrian Science Fund (FWF P 22073-B19) and the St Anna Kinderkrebsforschung to RP-G.

Author contributions

AI analyzed SNP arrays, compiled the data and drafted the manuscript; PZ and MZ performed CREBBP mutational screening; MM and RG performed additional experiments; BF and EF provided patient samples and clinical data; GM heads the Austrian BFM study and conceived the study; and OAH and RP-G conceived the study, supervised research and wrote the manuscript.

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Author notes

  1. O A Haas and R Panzer-Grümayer: These authors share senior authorship.

Authors and Affiliations

  1. Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria

    A Inthal, M Zeginigg, M Morak, R Grausenburger & R Panzer-Grümayer

  2. Medgen.at GmbH, Diagnostic Laboratory, Vienna, Austria

    P Zeitlhofer & O A Haas

  3. Department of Pediatric Haematology/Oncology, Laboratory of Molecular Genetics, 2nd Medical School, Charles University, Prague, Czech Republic

    E Fronkova

  4. Department of Pediatrics, St Anna Kinderspital, Medical University Vienna, Vienna, Austria

    B Fahrner, G Mann, O A Haas & R Panzer-Grümayer

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  1. A Inthal
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  2. P Zeitlhofer
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Correspondence to R Panzer-Grümayer.

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Supplementary Information accompanies the paper on the Leukemia website

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Inthal, A., Zeitlhofer, P., Zeginigg, M. et al. CREBBP HAT domain mutations prevail in relapse cases of high hyperdiploid childhood acute lymphoblastic leukemia. Leukemia 26, 1797–1803 (2012). https://doi.org/10.1038/leu.2012.60

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