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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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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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Correspondence to R Panzer-Grümayer.

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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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