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CREBBP mutations in relapsed acute lymphoblastic leukaemia

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.

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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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References

  1. Mullighan, C. G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758–764 (2007)

    Article  ADS  CAS  Google Scholar 

  2. 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)

    Article  CAS  Google Scholar 

  3. Mullighan, C. G. et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322, 1377–1380 (2008)

    Article  ADS  CAS  Google Scholar 

  4. Goodman, R. H. & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 (2000)

    CAS  PubMed  Google Scholar 

  5. Pui, C. H., Robison, L. L. & Look, A. T. Acute lymphoblastic leukaemia. Lancet 371, 1030–1043 (2008)

    Article  CAS  Google Scholar 

  6. Harrison, C. J. Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br. J. Haematol. 144, 147–156 (2009)

    Article  Google Scholar 

  7. Mullighan, C. G. et al. Deletion of IKZF1 and prognosis in Acute Lymphoblastic Leukemia. N. Engl. J. Med. 360, 470–480 (2009)

    Article  CAS  Google Scholar 

  8. Kuiper, R. P. et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia 24, 1258–1264 (2010)

    Article  CAS  Google Scholar 

  9. 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)

    Article  CAS  Google Scholar 

  10. Vo, N. & Goodman, R. H. CREB-binding protein and p300 in transcriptional regulation. J. Biol. Chem. 276, 13505–13508 (2001)

    Article  CAS  Google Scholar 

  11. Blobel, G. A. CREB-binding protein and p300: molecular integrators of hematopoietic transcription. Blood 95, 745–755 (2000)

    CAS  PubMed  Google Scholar 

  12. Yang, X. J. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res. 32, 959–976 (2004)

    Article  CAS  Google Scholar 

  13. Schorry, E. K. et al. Genotype-phenotype correlations in Rubinstein-Taybi syndrome. Am. J. Med. Genet. A. 146A, 2512–2519 (2008)

    Article  CAS  Google Scholar 

  14. Miller, R. W. & Rubinstein, J. H. Tumors in Rubinstein-Taybi syndrome. Am. J. Med. Genet. 56, 112–115 (1995)

    Article  CAS  Google Scholar 

  15. Kung, A. L. et al. Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev. 14, 272–277 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Iyer, N. G., Ozdag, H. & Caldas, C. p300/CBP and cancer. Oncogene 23, 4225–4231 (2004)

    Article  CAS  Google Scholar 

  17. Kishimoto, M. et al. Mutations and deletions of the CBP gene in human lung cancer. Clin. Cancer Res. 11, 512–519 (2005)

    CAS  PubMed  Google Scholar 

  18. 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)

    Article  CAS  Google Scholar 

  19. Radtke, I. et al. Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proc. Natl Acad. Sci. USA 106, 12944–12949 (2009)

    Article  ADS  CAS  Google Scholar 

  20. Mullighan, C. G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008)

    Article  ADS  CAS  Google Scholar 

  21. Mullighan, C. G. et al. Rearrangement of CRLF2 in B-progenitor- and Down syndrome-associated acute lymphoblastic leukemia. Nature Genet. 41, 1243–1246 (2009)

    Article  CAS  Google Scholar 

  22. Liu, X. et al. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451, 846–850 (2008)

    Article  ADS  CAS  Google Scholar 

  23. Kang-Decker, N. et al. Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency. Cancer Cell 5, 177–189 (2004)

    Article  CAS  Google Scholar 

  24. 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)

    Article  CAS  Google Scholar 

  25. 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)

    Article  CAS  Google Scholar 

  26. Dordelmann, M. et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 94, 1209–1217 (1999)

    CAS  PubMed  Google Scholar 

  27. Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 10.1038/nature09730 (this issue)

  28. Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nature Rev. Drug Discov. 5, 769–784 (2006)

    Article  CAS  Google Scholar 

  29. 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)

    Article  CAS  Google Scholar 

  30. 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)

    Article  CAS  Google Scholar 

  31. Drexler, H. G. The Leukemia-Lymphoma Cell Line Facts Book 1st edn (Academic Press, 2001)

    Google Scholar 

  32. Manabe, A. et al. Interleukin-4 induces programmed cell death (apoptosis) in cases of high-risk acute lymphoblastic leukemia. Blood 83, 1731–1737 (1994)

    CAS  PubMed  Google Scholar 

  33. Sherry, S. T. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 29, 308–311 (2001)

    Article  CAS  Google Scholar 

  34. 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)

    Article  CAS  Google Scholar 

  35. Ewing, B. & Green, P. Base-calling of automated sequencer traces using phred. II. Error probabilities. Genome Res. 8, 186–194 (1998)

    Article  CAS  Google Scholar 

  36. Zhang, J. et al. SNPdetector: a software tool for sensitive and accurate SNP detection. PLOS Comput. Biol. 1, e53 (2005)

    Article  ADS  Google Scholar 

  37. Zhang, J. et al. Systematic analysis of genetic alterations in tumors using Cancer Genome WorkBench (CGWB). Genome Res. 17, 1111–1117 (2007)

    Article  CAS  Google Scholar 

  38. 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)

    Article  CAS  Google Scholar 

  39. Bamford, S. et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer 91, 355–358 (2004)

    Article  CAS  Google Scholar 

  40. Gordon, D., Albajian, C. & Green, P. Consed: a graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998)

    Article  CAS  Google Scholar 

  41. 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)

    Article  CAS  Google Scholar 

  42. Berman, H., Henrick, K. & Nakamura, H. Announcing the worldwide Protein Data Bank. Nature Struct. Biol. 10, 980 (2003)

    Article  CAS  Google Scholar 

  43. DeLano, W. L. The PyMOL Molecular Graphics System. 〈http://www.pymol.org〉 (2002)

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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.

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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.

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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). https://doi.org/10.1038/nature09727

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