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Rearrangement of CRLF2 in B-progenitor– and Down syndrome–associated acute lymphoblastic leukemia

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

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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Figure 1: PAR1 deletion and P2RY8-CRLF2 fusion in B-progenitor ALL.
Figure 2: Transforming effects of P2RY8-CRLF2 and Jak mutations.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

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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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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.

Corresponding author

Correspondence to Charles 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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