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Segmental uniparental disomy as a recurrent mechanism for homozygous CEBPA mutations in acute myeloid leukemia

Leukemia volume 21, pages 2382–2384 (2007)Cite this article

The basic leucine zipper (bZIP) transcription factor CCAAT/enhancer-binding protein-α (C/EBPα), encoded by the CEBPA gene, is essential for myeloid development.1 In acute myeloid leukemia (AML), interference with C/EBPα function may occur through several mechanisms.2 Mutations in the CEBPA coding region itself are observed in approximately 8% of AML. These mutations either involve N-terminal frameshift abnormalities, leading to increased translation of a 30 kDa isoform with dominant-negative properties, or in-frame insertions or deletions disrupting the bZIP domain located in the C-terminus.2 In many cases of AML, both types of mutations are found in the same leukemic cell, frequently involving both alleles, that is N-terminal mutation of one allele and C-terminal disruption of the other. In a previous gene expression profiling (GEP) study of 285 cases of de novo AML, two expression clusters were highly associated with CEBPA mutations.3 The majority of CEBPA mutant tumors in these clusters carried both an N-terminal and a bZIP mutation. Interestingly, in three cases only one of the two types of mutations was present, while a wild-type allele appeared to be absent. Here, we combined fluorescence in situ hybridization (FISH) experiments with single nucleotide polymorphism (SNP) array hybridization to investigate two potential mechanistic explanations for the existence of homozygous CEBPA mutations in these particular cases: deletion of the wild-type allele, or uniparental disomy (UPD) as a result of mitotic recombination.4

CEBPA mutational analysis by PCR and nucleotide sequencing has been described.3 These analyses revealed 17 mutant specimens, of which 3 carried homozygous mutations, in the cohort of 285 cases of AML.3 Two leukemias harbored homozygous mutations in the CEBPA bZIP region, whereas in the other case the mutation was found in the N-terminus (Table 1).

Table 1 Characteristics of AML cases with homozygous CEBPA mutations
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Figure 1

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Acknowledgements

We thank Roel Verhaak for assistance in data analysis. This work was supported by a grant from the Dutch Cancer Society ‘Koningin Wilhelmina Fonds’.

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Authors and Affiliations

  1. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    B J Wouters, M A Sanders, S Lugthart, W M C Geertsma-Kleinekoort, B Löwenberg, P J M Valk & R Delwel

  2. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

    E van Drunen & H B Beverloo

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  1. B J Wouters
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  2. M A Sanders
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Correspondence to R Delwel.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Wouters, B., Sanders, M., Lugthart, S. et al. Segmental uniparental disomy as a recurrent mechanism for homozygous CEBPA mutations in acute myeloid leukemia. Leukemia 21, 2382–2384 (2007). https://doi.org/10.1038/sj.leu.2404795

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