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Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia


Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.

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Figure 1: EBF1 deletions in B-progenitor ALL.
Figure 2: PAX5 deletions in ALL.
Figure 3: PAX5 translocations in B-progenitor ALL.
Figure 4: Impaired function of PAX5 mutants.


  1. Greaves, M. F. & Wiemels, J. Origins of chromosome translocations in childhood leukaemia. Nature Rev. Cancer 3, 639–649 (2003)

    CAS  Article  Google Scholar 

  2. Peters, U. R. et al. Aberrant FHIT mRNA transcripts are present in malignant and normal haematopoiesis, but absence of FHIT protein is restricted to leukaemia. Oncogene 18, 79–85 (1999)

    CAS  Article  Google Scholar 

  3. Jackson, A. et al. Deletion of 6q16-q21 in human lymphoid malignancies: a mapping and deletion analysis. Cancer Res. 60, 2775–2779 (2000)

    CAS  PubMed  Google Scholar 

  4. Okuda, T. et al. Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia. Blood 85, 2321–2330 (1995)

    CAS  PubMed  Google Scholar 

  5. Raynaud, S. et al. The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. Blood 87, 2891–2899 (1996)

    CAS  PubMed  Google Scholar 

  6. Raimondi, S. C. et al. Acute lymphoblastic leukemias with deletion of 11q23 or a novel inversion (11)(p13q23) lack MLL gene rearrangements and have favorable clinical features. Blood 86, 1881–1886 (1995)

    CAS  PubMed  Google Scholar 

  7. Heerema, N. A. et al. Abnormalities of chromosome bands 13q12 to 13q14 in childhood acute lymphoblastic leukemia. J. Clin. Oncol. 18, 3837–3844 (2000)

    CAS  Article  Google Scholar 

  8. Cave, H. et al. Deletion of chromosomal region 13q14.3 in childhood acute lymphoblastic leukemia. Leukemia 15, 371–376 (2001)

    CAS  Article  Google Scholar 

  9. Lin, H. & Grosschedl, R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature 376, 263–267 (1995)

    ADS  CAS  Article  Google Scholar 

  10. Ehrich, M. et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc. Natl Acad. Sci. USA 102, 15785–15790 (2005)

    ADS  CAS  Article  Google Scholar 

  11. Nutt, S. L., Heavey, B., Rolink, A. G. & Busslinger, M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–562 (1999)

    ADS  CAS  Article  Google Scholar 

  12. Busslinger, M. Transcriptional control of early B cell development. Annu. Rev. Immunol. 22, 55–79 (2004)

    CAS  Article  Google Scholar 

  13. Ying, H., Healy, J. I., Goodnow, C. C. & Parnes, J. R. Regulation of mouse CD72 gene expression during B lymphocyte development. J. Immunol. 161, 4760–4767 (1998)

    CAS  PubMed  Google Scholar 

  14. Cazzaniga, G. et al. The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case. Cancer Res. 61, 4666–4670 (2001)

    CAS  PubMed  Google Scholar 

  15. Strehl, S., Konig, M., Dworzak, M. N., Kalwak, K. & Haas, O. A. PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13). Leukemia 17, 1121–1123 (2003)

    CAS  Article  Google Scholar 

  16. Bohlander, S. K. ETV6: a versatile player in leukemogenesis. Semin. Cancer Biol. 15, 162–174 (2005)

    CAS  Article  Google Scholar 

  17. Wlodarska, I. et al. FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations. Leukemia 19, 1299–1305 (2005)

    CAS  Article  Google Scholar 

  18. Bond, H. M. et al. Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse Evi3, is highly expressed in primitive human hematopoietic cells. Blood 103, 2062–2070 (2004)

    CAS  Article  Google Scholar 

  19. Hu, H. et al. Foxp1 is an essential transcriptional regulator of B cell development. Nature Immunol. 7, 819–826 (2006)

    CAS  Article  Google Scholar 

  20. Warming, S. et al. Evi3, a common retroviral integration site in murine B-cell lymphoma, encodes an EBFAZ-related Kruppel-like zinc finger protein. Blood 101, 1934–1940 (2003)

    CAS  Article  Google Scholar 

  21. Garvie, C. W., Hagman, J. & Wolberger, C. Structural studies of Ets-1/Pax5 complex formation on DNA. Mol. Cell 8, 1267–1276 (2001)

    CAS  Article  Google Scholar 

  22. Czerny, T. & Busslinger, M. DNA-binding and transactivation properties of Pax-6: three amino acids in the paired domain are responsible for the different sequence recognition of Pax-6 and BSAP (Pax-5). Mol. Cell. Biol. 15, 2858–2871 (1995)

    CAS  Article  Google Scholar 

  23. Maier, H., Colbert, J., Fitzsimmons, D., Clark, D. R. & Hagman, J. Activation of the early B-cell-specific mb-1 (Ig-alpha) gene by Pax-5 is dependent on an unmethylated Ets binding site. Mol. Cell. Biol. 23, 1946–1960 (2003)

    CAS  Article  Google Scholar 

  24. Nutt, S. L., Morrison, A. M., Dorfler, P., Rolink, A. & Busslinger, M. Identification of BSAP (Pax-5) target genes in early B-cell development by loss- and gain-of-function experiments. EMBO J. 17, 2319–2333 (1998)

    CAS  Article  Google Scholar 

  25. Ross, M. E. et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 102, 2951–2959 (2003)

    CAS  Article  Google Scholar 

  26. Martoriati, A. et al. dapk1, encoding an activator of a p19ARF-p53-mediated apoptotic checkpoint, is a transcription target of p53. Oncogene 24, 1461–1466 (2005)

    CAS  Article  Google Scholar 

  27. Conte, N. et al. Carcinogenesis and translational controls: TACC1 is down-regulated in human cancers and associates with mRNA regulators. Oncogene 21, 5619–5630 (2002)

    CAS  Article  Google Scholar 

  28. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005)

    ADS  CAS  Article  Google Scholar 

  29. Georgopoulos, K. et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 79, 143–156 (1994)

    CAS  Article  Google Scholar 

  30. O’Riordan, M. & Grosschedl, R. Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. Immunity 11, 21–31 (1999)

    Article  Google Scholar 

  31. Winandy, S., Wu, P. & Georgopoulos, K. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma. Cell 83, 289–299 (1995)

    CAS  Article  Google Scholar 

  32. Nutt, S. L. et al. Independent regulation of the two Pax5 alleles during B-cell development. Nature Genet. 21, 390–395 (1999)

    CAS  Article  Google Scholar 

  33. Robson, E. J., He, S. J. & Eccles, M. R. A. PANorama of PAX genes in cancer and development. Nature Rev. Cancer 6, 52–62 (2006)

    CAS  Article  Google Scholar 

  34. Busslinger, M., Klix, N., Pfeffer, P., Graninger, P. G. & Kozmik, Z. Deregulation of PAX-5 by translocation of the Eμ enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma. Proc. Natl Acad. Sci. USA 93, 6129–6134 (1996)

    ADS  CAS  Article  Google Scholar 

  35. Matsuzaki, H. et al. Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. Nature Methods 1, 109–111 (2004)

    CAS  Article  Google Scholar 

  36. Lin, M. et al. dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 20, 1233–1240 (2004)

    CAS  Article  Google Scholar 

  37. Olshen, A. B., Venkatraman, E. S., Lucito, R. & Wigler, M. Circular binary segmentation for the analysis of array-based DNA copy number data. Biostatistics 5, 557–572 (2004)

    Article  Google Scholar 

  38. McCarroll, S. A. et al. Common deletion polymorphisms in the human genome. Nature Genet. 38, 86–92 (2006)

    CAS  Article  Google Scholar 

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We thank Z. Cai and L. King for technical assistance; B. Schulman for modelling of PAX5 mutations; M. Roussel, M. Busslinger and J. Hagman for providing reagents; the Tumor Processing Laboratory of SJCRH for providing tumour samples; and C. Li for discussions and modifications of dChipSNP. This work was supported by grants from the National Cancer Institute (to J.R.D. and W.E.E.), the National Institute of General Medical Sciences (to M.V.R.), the National Health and Medical Research Council (Australia) (to C.G.M.), the Royal Australasian College of Physicians (to C.G.M.), the Haematology Society of Australia and New Zealand (to C.G.M), and the American Lebanese and Syrian Associated Charities (ALSAC) of SJCRH.

Author Contributions J.R.D. designed and supervised experiments. C.G.M, S.G., I.R, C.B.M., E.C.-S., J.D.D and K.G. performed experiments. S.A.S. collected and managed clinical samples and data. C.G.M., S.G., J.M., S.B.P. and X.S. analysed data. S.B.P. developed software for DNA copy number analysis. C.-H.P., M.V.R. and W.E.E. provided patient samples. C.G.M. and J.R.D. wrote the manuscript. All authors discussed the results and commented on the manuscript.

The primary SNP microarray data have been deposited in NCBIs Gene Expression Omnibus (GEO, and are accessible through GEO Series accession number GSE5511. The data are also available at Sequences of the PAX5 fusion transcripts have been deposited in GenBank with accessions DQ841178 (PAX5–ETV6), DQ845346 (PAX5–FOXP1) and DQ845345 (PAX5–ZNF521).

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Correspondence to James R. Downing.

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Supplementary Information

This file contains Supplementary Methods, Supplementary Results, Supplementary Tables 1-24, Supplementary Figures 1-33 with Legends and additional references (PDF 5365 kb)

Supplementary S-Plus files

This archive contains two S-Plus files that are the basis for the karyotype-guided SNP array normalization algorithm described in the Supplementary Methods. These can be opened by a text editor, (ZIP 5 kb)

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

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