Chromosome 21q22 Triplication Promotes B-Cell Transformation

Individuals with Down syndrome (trisomy 21) have a significantly increased risk of B-cell acute lymphoblastic leukemia (B-ALL), and polysomy 21 is the most common aneuploidy in B-ALL. To gain insight into why extra copies of chromosome 21 are associated with B-ALL, Lane and colleagues evaluated B-cell development in transgenic mice harboring a chromosomal triplication orthologous to a region of chromosome 21q22 that is recurrently amplified in B-ALL. Triplication of this region, which contains only 31 genes, led to B-cell maturation defects, conferred B cells with the ability to self-renew, and accelerated leukemogenesis induced by either BCR–ABL or alterations of CRLF2 and JAK2. Differentially expressed genes induced by 21q22 triplication in mice were enriched among gene signatures of Down syndrome–associated B-ALLs and were highly enriched for Polycomb repressor complex 2 targets and histone H3 lysine 27 trimethylation (H3K27me3) sites. Global H3K27me3 loss was also observed in 21q22 transgenic B cells, and overexpressed genes were highly enriched for those normally bivalently marked with H3K27me3 and H3K4me3. Notably, restoration of H3K27me3 with an H3K27 demethylase inhibitor reduced self-renewal of the transgenic B cells and was toxic to Down syndrome–associated B-ALL cells, raising the possibility that inhibition of H3K27 demethylases may have therapeutic benefit in B-ALLs harboring extra copies of chromosome 21q22. Overexpression of one gene in this region, high mobility group nucleosome binding domain 1 (Hmgn1), led to a reduction in global H3K27me3 levels and was required for self-renewal of 21q22 transgenic B cells, and transgenic overexpression of human HMGN1 in mice blocked B-cell differentiation, promoted B-cell self-renewal, and shortened the latency of BCR–ABL-induced B-ALL. Together, these findings suggest that the association between B-ALL and trisomy or polysomy 21 may be attributable to H3K27me3 loss caused by overexpression of a small number of genes on chromosome 21, including HMGN1.

Lane AA, Chapuy B, Lin CY, Tivey T, Li H, Townsend EC, et al. Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation. Nat Genet 2014 Apr 20 [Epub ahead of print].

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