Rearrangement of CRLF2 in B-progenitor– and Down syndrome–associated acute lymphoblastic leukemia (original) (raw)

• Letter
• Published: 18 October 2009
• J Racquel Collins-Underwood1,
• Letha A A Phillips1,
• Michael G Loudin2,
• Wei Liu3,
• Jinghui Zhang4,
• Jing Ma5,
• Elaine Coustan-Smith6,
• Richard C Harvey7,
• Cheryl L Willman7,
• Fady M Mikhail8,
• Julia Meyer9,
• Andrew J Carroll8,
• Richard T Williams6,
• Jinjun Cheng1,
• Nyla A Heerema10,
• Giuseppe Basso11,
• Andrea Pession12,
• Ching-Hon Pui6,
• Susana C Raimondi1,
• Stephen P Hunger13,
• James R Downing1,
• William L Carroll9 &
• …
• Karen R Rabin2

Nature Genetics volume 41, pages 1243–1246 (2009)Cite this article

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Abstract

Aneuploidy and translocations are hallmarks of B-progenitor acute lymphoblastic leukemia (ALL), but many individuals with this cancer lack recurring chromosomal alterations. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that juxtaposes the first, noncoding exon of P2RY8 with the coding region of CRLF2. We identified the P2RY8-CRLF2 fusion in 7% of individuals with B-progenitor ALL and 53% of individuals with ALL associated with Down syndrome. CRLF2 alteration was associated with activating JAK mutations, and expression of human P2RY8-CRLF2 together with mutated mouse Jak2 resulted in constitutive Jak-Stat activation and cytokine-independent growth of Ba/F3 cells overexpressing interleukin-7 receptor alpha. Our findings indicate that these two genetic lesions together contribute to leukemogenesis in B-progenitor ALL.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

References

1. Pui, C.H., Robison, L.L. & Look, A.T. Acute lymphoblastic leukaemia. Lancet 371, 1030–1043 (2008).
   Article CAS Google Scholar
2. Mullighan, C.G. et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446, 758–764 (2007).
   Article CAS Google Scholar
3. Mullighan, C.G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008).
   Article CAS Google Scholar
4. Forestier, E. et al. Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome: an iBFM-SG study. Blood 111, 1575–1583 (2008).
   Article CAS Google Scholar
5. Whitlock, J.A. Down syndrome and acute lymphoblastic leukaemia. Br. J. Haematol. 135, 595–602 (2006).
   Article Google Scholar
6. Malinge, S., Izraeli, S. & Crispino, J.D. Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113, 2619–2628 (2009).
   Article CAS Google Scholar
7. Rochman, Y. & Leonard, W.J. Thymic stromal lymphopoietin: a new cytokine in asthma. Curr. Opin. Pharmacol. 8, 249–254 (2008).
   Article CAS Google Scholar
8. Ziegler, S.F. & Liu, Y.J. Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat. Immunol. 7, 709–714 (2006).
   Article CAS Google Scholar
9. Fujiwara, S. et al. Transforming activity of purinergic receptor P2Y, G protein coupled, 8 revealed by retroviral expression screening. Leuk. Lymphoma 48, 978–986 (2007).
   Article CAS Google Scholar
10. Storlazzi, C.T. et al. Upregulation of the SOX5 gene by promoter swapping with the P2RY8 gene in primary splenic follicular lymphoma. Leukemia 21, 2221–2225 (2007).
    Article CAS Google Scholar
11. Russell, L.J. et al. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B cell precursor acute lymphoblastic leukemia. Blood 114, 2688–2698 (2009).
    Article CAS Google Scholar
12. Marculescu, R. et al. Recombinase, chromosomal translocations and lymphoid neoplasia: targeting mistakes and repair failures. DNA Repair (Amst.) 5, 1246–1258 (2006).
    Article CAS Google Scholar
13. Bercovich, D. et al. Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome. Lancet 372, 1484–1492 (2008).
    Article CAS Google Scholar
14. Kearney, L. et al. A specific JAK2 mutation (JAK2R683) and multiple gene deletions in Down syndrome acute lymphoblastic leukaemia. Blood 113, 646–648 (2009).
    Article CAS Google Scholar
15. Gaikwad, A. et al. Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br. J. Haematol. 144, 930–932 (2009).
    Article CAS Google Scholar
16. Mullighan, C.G. et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 106, 9414–9418 (2009).
    Article CAS Google Scholar
17. Hasle, H., Clemmensen, I.H. & Mikkelsen, M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355, 165–169 (2000).
    Article CAS Google Scholar
18. Graux, C. et al. Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat. Genet. 36, 1084–1089 (2004).
    Article CAS Google Scholar
19. Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol. 6, 1047–1053 (2005).
    Article CAS Google Scholar
20. Carpino, N. et al. Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development. Mol. Cell. Biol. 24, 2584–2592 (2004).
    Article CAS Google Scholar
21. Parrish, Y.K. et al. IL-7 Dependence in human B lymphopoiesis increases during progression of ontogeny from cord blood to bone marrow. J. Immunol. 182, 4255–4266 (2009).
    Article CAS Google Scholar
22. Isaksen, D.E. et al. Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction. J. Immunol. 163, 5971–5977 (1999).
    CAS PubMed Google Scholar
23. Levine, R.L. & Gilliland, D.G. Myeloproliferative disorders. Blood 112, 2190–2198 (2008).
    Article CAS Google Scholar
24. Mullighan, C.G. et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 322, 1377–1380 (2008).
    Article CAS Google Scholar
25. 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
26. Pounds, S. et al. Reference alignment of SNP microarray signals for copy number analysis of tumors. Bioinformatics 25, 315–321 (2009).
    Article CAS Google Scholar
27. Smyth, G.K. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article 3 (2004).
    Article Google Scholar
28. Venkatraman, E.S. & Olshen, A.B. A faster circular binary segmentation algorithm for the analysis of array CGH data. Bioinformatics 23, 657–663 (2007).
    Article CAS Google Scholar
29. Hanawa, H. et al. Comparison of various envelope proteins for their ability to pseudotype lentiviral vectors and transduce primitive hematopoietic cells from human blood. Mol. Ther. 5, 242–251 (2002).
    Article CAS Google Scholar
30. Mantel, N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep. 50, 163–170 (1966).
    CAS PubMed Google Scholar
31. Peto, R. et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br. J. Cancer 35, 1–39 (1977).
    Article CAS Google Scholar
32. Gray, R.J. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann. Stat. 16, 1141–1154 (1988).
    Article Google Scholar
33. Fine, J.P. & Gray, R.J. A proportional hazards model for the subdistribution of a competing risk. J. Am. Stat. Assoc. 94, 496–509 (1999).
    Article Google Scholar

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Acknowledgements

We thank M. Wang and D. Naeve (Functional Genomics Laboratory, Hartwell Center, St. Jude Children's Research Hospital) for conducting array-CGH analysis; E. Walker and J. Morris (CACT Laboratory, Hartwell Center) for conducting SNP microarrays; S. Tate, J. Armstrong and K. Rakestraw (St. Jude Hartwell Center Sequencing Core) for conducting sequencing; the St. Jude Flow Cytometry Core; John Gray and the St. Jude Vector Core for lentiviral reagents and methods; the St. Jude Tissue Resources Laboratory for providing primary patient samples; S. Nutt for providing the MSCV-mIL7R-IRES-hCD4 retroviral vector; G.P. Nolan, Stanford University, for the Eco Phoenix packaging cells (http://www.stanford.edu/group/nolan); and M. Smith and K. Dobbin for gene expression studies of CRLF2. This work was supported by National Cancer Institute Cancer Center Support Grant P30 CA021765, the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital, a Bear Necessities Pediatric Research Foundation grant (to K.R.R.), a Children's Cancer Research Foundation grant (to K.R.R.) and National Institutes of Health Pediatric Oncology Clinical Research Training Grant CA90433-06 (to K.R.R.).

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Authors and Affiliations

1. Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
   Charles G Mullighan, J Racquel Collins-Underwood, Letha A A Phillips, Jinjun Cheng, Susana C Raimondi & James R Downing
2. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA
   Michael G Loudin & Karen R Rabin
3. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
   Wei Liu
4. Center for Biomedical Informatics and Information Technology, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
   Jinghui Zhang
5. The Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
   Jing Ma
6. Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
   Elaine Coustan-Smith, Richard T Williams & Ching-Hon Pui
7. University of New Mexico Cancer Research & Treatment Center, University of New Mexico Cancer Research Facility, Albuquerque, New Mexico, USA
   Richard C Harvey & Cheryl L Willman
8. Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA
   Fady M Mikhail & Andrew J Carroll
9. New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA
   Julia Meyer & William L Carroll
10. Department of Pathology, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
    Nyla A Heerema
11. Department of Pediatrics, University of Padua, Padua, Italy
    Giuseppe Basso
12. Department of Pediatrics, University of Bologna, Hematology and Oncology Unit 'Lalla Seràgnoli', Bologna, Italy
    Andrea Pession
13. Section of Pediatric Hematology, Oncology and Bone Marrow Transplantation and Center for Cancer and Blood Disorders, University of Colorado Denver School of Medicine, The Children's Hospital, Aurora, Colorado, USA
    Stephen P Hunger

Authors

1. Charles G Mullighan
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2. J Racquel Collins-Underwood
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3. Letha A A Phillips
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4. Michael G Loudin
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5. Wei Liu
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6. Jinghui Zhang
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7. Jing Ma
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8. Elaine Coustan-Smith
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9. Richard C Harvey
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10. Cheryl L Willman
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11. Fady M Mikhail
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12. Julia Meyer
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13. Andrew J Carroll
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14. Richard T Williams
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15. Jinjun Cheng
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16. Nyla A Heerema
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17. Giuseppe Basso
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18. Andrea Pession
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19. Ching-Hon Pui
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20. Susana C Raimondi
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21. Stephen P Hunger
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22. James R Downing
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23. William L Carroll
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24. Karen R Rabin
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Contributions

C.G.M. designed and coordinated the study, designed assays, conducted experiments, analyzed data and wrote the manuscript. J.R.C.-U. generated retroviral vectors and conducted Ba/F3 assays. L.A.A.P. conducted JAK sequencing and quantitative PCR assays. M.L.L. conducted PAR1 deletion genomic PCR. W.L. conducted statistical analysis. J.Z. analyzed sequencing data. J. Ma analyzed microarray data. E.C.-S. conducted flow cytometry and analyzed data. R.C.H. and C.L.W. developed FISH assays. J. Meyer conducted experiments and analyzed data. F.M.M., A.J.C. and N.A.H. conducted FISH assays and analyzed cytogenetic data. R.T.W. provided luciferase vectors. J.C. designed subcloning vectors. G.B., A.P., C.-H.P. and J.R.D. provided patient samples. S.C.R. conducted cytogenetic analysis. S.P.H. coordinated studies and sample collection. W.L.C. provided patient samples, conducted experiments and analyzed data. K.R.R. provided samples, conducted experiments and analyzed data.

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Correspondence toCharles G Mullighan.

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Mullighan, C., Collins-Underwood, J., Phillips, L. et al. Rearrangement of CRLF2 in B-progenitor– and Down syndrome–associated acute lymphoblastic leukemia.Nat Genet 41, 1243–1246 (2009). https://doi.org/10.1038/ng.469

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• Received: 06 July 2009
• Accepted: 18 September 2009
• Published: 18 October 2009
• Issue Date: November 2009
• DOI: https://doi.org/10.1038/ng.469

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