Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Mullighan, C. G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758–764 (2007)
Kuiper, R. P. et al. High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 21, 1258–1266 (2007)
Mullighan, C. G. et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322, 1377–1380 (2008)
Goodman, R. H. & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 (2000)
Pui, C. H., Robison, L. L. & Look, A. T. Acute lymphoblastic leukaemia. Lancet 371, 1030–1043 (2008)
Harrison, C. J. Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br. J. Haematol. 144, 147–156 (2009)
Mullighan, C. G. et al. Deletion of IKZF1 and prognosis in Acute Lymphoblastic Leukemia. N. Engl. J. Med. 360, 470–480 (2009)
Kuiper, R. P. et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia 24, 1258–1264 (2010)
Yang, J. J. et al. Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. Blood 112, 4178–4183 (2008)
Vo, N. & Goodman, R. H. CREB-binding protein and p300 in transcriptional regulation. J. Biol. Chem. 276, 13505–13508 (2001)
Blobel, G. A. CREB-binding protein and p300: molecular integrators of hematopoietic transcription. Blood 95, 745–755 (2000)
Yang, X. J. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 32, 959–976 (2004)
Schorry, E. K. et al. Genotype-phenotype correlations in Rubinstein-Taybi syndrome. Am. J. Med. Genet. A. 146A, 2512–2519 (2008)
Miller, R. W. & Rubinstein, J. H. Tumors in Rubinstein-Taybi syndrome. Am. J. Med. Genet. 56, 112–115 (1995)
Kung, A. L. et al. Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev. 14, 272–277 (2000)
Iyer, N. G., Ozdag, H. & Caldas, C. p300/CBP and cancer. Oncogene 23, 4225–4231 (2004)
Kishimoto, M. et al. Mutations and deletions of the CBP gene in human lung cancer. Clin. Cancer Res. 11, 512–519 (2005)
Shigeno, K. et al. Disease-related potential of mutations in transcriptional cofactors CREB-binding protein and p300 in leukemias. Cancer Lett. 213, 11–20 (2004)
Radtke, I. et al. Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proc. Natl Acad. Sci. USA 106, 12944–12949 (2009)
Mullighan, C. G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008)
Mullighan, C. G. et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nature Genet. 41, 1243–1246 (2009)
Liu, X. et al. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451, 846–850 (2008)
Kang-Decker, N. et al. Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency. Cancer Cell 5, 177–189 (2004)
Kasper, L. H. et al. Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development. Mol. Cell. Biol. 26, 789–809 (2006)
Kasper, L. H. et al. CBP/p300 double null cells reveal effect of coactivator level and diversity on CREB transactivation. EMBO J. 29, 3660–3672 (2010)
Dordelmann, M. et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 94, 1209–1217 (1999)
Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 10.1038/nature09730 (this issue)
Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nature Rev. Drug Discov. 5, 769–784 (2006)
Tsapis, M. et al. HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway. Int. J. Biochem. Cell Biol. 39, 1500–1509 (2007)
Bordoli, L. et al. Functional analysis of the p300 acetyltransferase domain: the PHD finger of p300 but not of CBP is dispensable for enzymatic activity. Nucleic Acids Res. 29, 4462–4471 (2001)
Drexler, H. G. The Leukemia-Lymphoma Cell Line Facts Book 1st edn (Academic Press, 2001)
Manabe, A. et al. Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia. Blood 83, 1731–1737 (1994)
Sherry, S. T. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29, 308–311 (2001)
Ewing, B., Hillier, L., Wendl, M. C. & Green, P. Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res. 8, 175–185 (1998)
Ewing, B. & Green, P. Base-calling of automated sequencer traces using phred. II. Error probabilities. Genome Res. 8, 186–194 (1998)
Zhang, J. et al. SNPdetector: a software tool for sensitive and accurate SNP detection. PLOS Comput. Biol. 1, e53 (2005)
Zhang, J. et al. Systematic analysis of genetic alterations in tumors using Cancer Genome WorkBench (CGWB). Genome Res. 17, 1111–1117 (2007)
Zhang, J., Rowe, W. L., Struewing, J. P. & Buetow, K. H. HapScope: a software system for automated and visual analysis of functionally annotated haplotypes. Nucleic Acids Res. 30, 5213–5221 (2002)
Bamford, S. et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 91, 355–358 (2004)
Gordon, D., Albajian, C. & Green, P. Consed: a graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998)
Andrews, N. C. & Faller, D. V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 19, 2499 (1991)
Berman, H., Henrick, K. & Nakamura, H. Announcing the worldwide Protein Data Bank. Nature Struct. Biol. 10, 980 (2003)
DeLano, W. L. The PyMOL Molecular Graphics System. 〈http://www.pymol.org〉 (2002)
Acknowledgements
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
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
The file contains Supplementary Results, Supplementary Tables 1-7, Supplementary Figures 1-12 with legends and additional references. (PDF 1392 kb)
PowerPoint slides
Rights and permissions
About this article
Cite this article
Mullighan, C., Zhang, J., Kasper, L. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011). https://doi.org/10.1038/nature09727
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature09727
This article is cited by
-
Chromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia
Nature Communications (2023)
-
Dasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia
Nature Communications (2023)
-
miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease
Leukemia (2023)
-
Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia
Leukemia (2023)
-
TAZ2 truncation confers overactivation of p300 and cellular vulnerability to HDAC inhibition
Nature Communications (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.