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Novel ALK fusion in anaplastic large cell lymphoma involving EEF1G, a subunit of the eukaryotic elongation factor-1 complex

Leukemia volume 31, pages 743–747 (2017)Cite this article

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Anaplastic large cell lymphoma (ALCL) in children is frequently associated with a translocation in the anaplastic lymphoma kinase (ALK) gene at the 2p23 locus. In ALK-positive ALCL (ALK+ ALCL), the major fusion partner is nucleophosmin 1 (NPM1), which results in the translocation t(2;5)(p23;q35) and aberrant production of the 80 kDa fusion protein NPM1–ALK.1 ALK kinase belongs to the insulin receptor subfamily of kinases and is expressed in only the neuronal tissue, ganglion cells of the intestine and testis. However, translocation with NPM1 or alternative partners leads to aberrant constitutive activation of the catalytic domain of ALK through homodimerization.2 For the most common NPM1–ALK fusion, immunohistochemical detection of the ALK antigen shows both nuclear and cytoplasmic staining due to the heterodimerization of NPM1–ALK and normal NPM1, a nucleolar phosphoprotein that is ubiquitously expressed and shuttles between the cytoplasm and the nucleus.3 ~15% of ALK+ ALCL cases lack the nuclear staining pattern, indicating that aberrant ALK expression is due to a partner gene other than NPM1. Indeed, in some ALK+ ALCL cases, a different partner for ALK has been identified, such as TPM3, TFG, ATIC, CLTCL, MSN, MYH9, or TRAF.4, 5 Herein, we report a novel translocation partner for ALK in two pediatric patients with ALCL by using next-generation transcriptome sequencing analysis.

To assess the frequency of the novel EEF1G–ALK fusion gene in ALK+ ALCL, the RNA-seq data from 27 additional pediatric patients with ALCL were studied to determine the presence of the ALK fusion. In this group that also included patient 1 described above (n=28), all patients harbored an ALK fusion, of whom four (14.3%) had a variant non-NPM1–ALK fusion. The identified partner genes included the novel ALK partner EEF1G in one more case (patient 2) and the known partner ATIC (2q35) in two patients. Immunohistochemical staining for ALK expression in tumor tissues from these four patients revealed a cytoplasmic-only ALK staining pattern, which was consistent with the presence of a variant t(2p23/ALK) (Supplementary Figure S1). Wild-type or full-length ALK mRNA was not detected.

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Acknowledgements

We thank the Children’s Oncology Group and the Children’s Cancer and Leukaemia Group (CCLG) Tissue Bank for access to specimens. The CCLG Tissue Bank is funded by Cancer Research UK and CCLG. This work was supported in part by ALSAC and by the National Cancer Institute Grant CA21765 (St Jude Children’s Research Hospital Cancer Center Support Grant). We thank the staff of the Hartwell Center for Bioinformatics and Biotechnology, the Flow Cytometry and Cell Sorting Core Facility, and the Cell and Tissue Imaging Facility at St Jude Children's Research Hospital.

Author contributions

GP performed the experiments and contributed to the writing of the manuscript; TS and YL interpreted the RNA-seq data; RKS, CGM, and MSL contributed to reagent preparation and assisted in preparation of the manuscript; JTS assisted with the writing of the paper; MV performed and analyzed FISH data and VL designed the research, analyzed the data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA

    G Palacios, C G Mullighan & V Leventaki

  2. Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, TN, USA

    T I Shaw & Y Li

  3. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

    R K Singh

  4. Department of Cytogenetics, St Jude Children’s Research Hospital, Memphis, TN, USA

    M Valentine

  5. Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, USA

    J T Sandlund

  6. Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA

    M S Lim

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  1. G Palacios
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Correspondence to V Leventaki.

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Palacios, G., Shaw, T., Li, Y. et al. Novel ALK fusion in anaplastic large cell lymphoma involving EEF1G, a subunit of the eukaryotic elongation factor-1 complex. Leukemia 31, 743–747 (2017). https://doi.org/10.1038/leu.2016.331

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