CREBBP mutations in relapsed acute lymphoblastic leukaemia


Relapsed acute lymphoblastic leukaemia (ALL) is a leading cause of death due to disease in young people, but the biological determinants of treatment failure remain poorly understood. Recent genome-wide profiling of structural DNA alterations in ALL have identified multiple submicroscopic somatic mutations targeting key cellular pathways1,2, and have demonstrated substantial evolution in genetic alterations from diagnosis to relapse3. However, DNA sequence mutations in ALL have not been analysed in detail. To identify novel mutations in relapsed ALL, we resequenced 300 genes in matched diagnosis and relapse samples from 23 patients with ALL. This identified 52 somatic non-synonymous mutations in 32 genes, many of which were novel, including the transcriptional coactivators CREBBP and NCOR1, the transcription factors ERG, SPI1, TCF4 and TCF7L2, components of the Ras signalling pathway, histone genes, genes involved in histone modification (CREBBP and CTCF), and genes previously shown1,2 to be targets of recurring DNA copy number alteration in ALL. Analysis of an extended cohort of 71 diagnosis–relapse cases and 270 acute leukaemia cases that did not relapse found that 18.3% of relapse cases had sequence or deletion mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CREBBP, also known as CBP)4. The mutations were either present at diagnosis or acquired at relapse, and resulted in truncated alleles or deleterious substitutions in conserved residues of the histone acetyltransferase domain. Functionally, the mutations impaired histone acetylation and transcriptional regulation of CREBBP targets, including glucocorticoid responsive genes. Several mutations acquired at relapse were detected in subclones at diagnosis, suggesting that the mutations may confer resistance to therapy. These results extend the landscape of genetic alterations in leukaemia, and identify mutations targeting transcriptional and epigenetic regulation as a mechanism of resistance in ALL.

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Figure 1: CREBBP sequence mutations in relapsed ALL.
Figure 2: CREBBP mutations impair histone acetylation and multiple gene expression programs.


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We thank T. Jeevan, S. Orwick and A. Gibson for technical assistance, B. Schulman for assistance with structural modelling, and B. Woolf and J. Hartigan of Beckman Coulter Genomics for assistance with sequencing. We thank the Tissue Resources Facility of St Jude Children’s Research Hospital for providing samples, and the following St Jude core facilities: Vector Development and Production, Flow Cytometry and Cell Sorting, Cell and Tissue Imaging, the Animal Resource Center, and the DNA sequencing and Macromolecular Synthesis laboratories of the Hartwell Center for Bioinformatics and Biotechnology. This study was supported by ALSAC of St Jude and Cancer Center support grant P30 CA021765, and grant number DE018183 (P.K.B.). C.G.M. is a Pew Scholar in the Biomedical Sciences.

Author information

C.G.M., P.K.B. and J.R.D. designed the study. S.L.H., L.H., C.G.M., L.A.P. and D.P.-T. performed PCR and sequencing. J.Z. and K.H.B. analysed sequence data. L.H.K. and S.L. performed in vitro assays of the functional activity of Crebbp mutants. J.M. analysed genomic data. S.L.H. and J.R.C.-U. performed cell line assays. S.D.B. designed and performed leukaemia cell line drug responsiveness assays. C.-H.P. provided samples and clinical data. C.G.M. wrote the manuscript. All authors reviewed the manuscript.

Correspondence to Charles G. Mullighan.

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Mullighan, C., Zhang, J., Kasper, L. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011).

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