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Haematological cancer

Down syndrome links to cancer

Nature Reviews Clinical Oncology volume 11, page 303 (2014)Cite this article

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Children with Down syndrome (DS or trisomy 21), have a 20-fold increased risk of developing B-cell acute lymphoblastic leukaemia (B-ALL) as chromosome 21 is also the most frequently gained chromosome in patients with B-ALL without DS. However, the mechanisms underlying the role of chromosome 21 triplication in leukaemia development are unclear. A new study by Andrew Lane and colleagues reports that overexpression of the nucleosome remodeller non-histone chromosomal protein HMG-14 (HMGN1) and changes in chromatin methylation are key events in the development of DS-related B-ALL.

The researchers studied B-cell development and leukemogenesis in a mouse model of DS in which only 31 genes of the human chromosome 21 were triplicated. “This region overlapped with a recurrent intrachromosomal amplification that is seen in patients with B-ALL and is associated with a very poor prognosis,” explains Lane. Mouse B cells and human B-ALL cells with trisomy 21 showed transcriptional upregulation of targets of the polycomb repressor complex 2 (PRC2). In addition, “trisomy 21 mouse B cells had decreased histone H3K27 trimethylation—the repressive mark normally placed by PRC2,” says Lane. The researchers reported that inhibitors of H3K27 histone demethylases block the growth of trisomy 21 B cells, and treatment of wild-type B cells with a PRC2 inhibitor was sufficient to confer self-renewal activity. As Lane emphasizes, “these data suggest that progenitor B-cell growth is modulated by H3K27 methylation status, and that trisomy 21 may alter B-cell phenotypes by disrupting this epigenetic regulation.”

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References

  1. Lane, A. A. et al. Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nat. Genet. 10.1038/ng.2949

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  1. Alessia Errico
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Letorneau, A. et al. Domains of genome-wide gene expression dysregulation in Down's syndrome. Nature

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Errico, A. Down syndrome links to cancer. Nat Rev Clin Oncol 11, 303 (2014). https://doi.org/10.1038/nrclinonc.2014.84

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