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Lymphoma

Targetability of STAT3-JAK2 fusions: implications for T-cell lymphoproliferative disorders of the gastrointestinal tract

Leukemia volume 34, pages 1467–1471 (2020)Cite this article

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The growth and survival of T cells broadly depend on JAK-STAT signaling, and dysregulation of this pathway is common and potentially targetable in a variety of T-cell lymphoproliferative disorders and lymphomas [1, 2]. We previously identified novel and recurrent STAT3-JAK2 fusion genes associated with t(9;17)(p24.1;q21.2) in patients with T-cell lymphoproliferative disorder of the gastrointestinal tract (GI TLPD) [3], a new provisional entity in the 2017 revision of the World Health Organization (WHO) classification of lymphoid neoplasms [4]. GI TLPD is characterized by debilitating gastrointestinal symptoms and a chronic, relapsing course. It is often refractory to both symptomatic management and conventional chemotherapy regimens. While characterized as an indolent lymphoproliferative disorder, some cases transform into overt T-cell lymphomas, particularly those with a CD4-positive phenotype [4]. We reported STAT3-JAK2 fusions in four of five CD4-positive GI TLPDs but not in cases with other phenotypes, and one patient with STAT3-JAK2 underwent fatal large-cell transformation [3]. The fusion transcript encoded a fusion protein containing most of STAT3 and the JAK homology 1 tyrosine kinase domain of JAK2, and was associated with immunohistochemical detection of phosphorylated (p) STAT5Y694 but not pSTAT3Y705. The recurrence of the fusion and the chronic, refractory nature of GI TLPDs prompted us to characterize the function and targetability of STAT3-JAK2.

We then evaluated the intracellular effects of STAT3-JAK2 in HEK-293 cells, which lack baseline activation of JAK2, STAT3, and STAT5 (Supplementary Fig. 2a). STAT3-JAK2 expression resulted in phosphorylation of the residues within the fusion corresponding to JAK2Y1007/1008 and STAT3Y705 and phosphorylation of native STAT3Y705 and STAT5Y694. STAT3-JAK2 also resulted in phosphorylation of native STAT3 and STAT5 in TLBR-3 cells, with preferential phosphorylation of STAT5 (Supplementary Fig. 2b). Using a JAK2 kinase activity assay, we then demonstrated that purified HA-tagged STAT3-JAK2, but not kinase-dead STAT3-JAK2K882E, had intrinsic kinase activity (Supplementary Fig. 3a). Furthermore, purified STAT3-JAK2 but not STAT3-JAK2K882E directly phosphorylated recombinant STAT3 and STAT5 (Supplementary Fig. 3b). Finally, native STAT3 and STAT5 were co-immunoprecipitated with HA-STAT3-JAK2 (Supplementary Fig. 3c). These data suggest STAT3-JAK2 directly interacts with STAT3 and STAT5 and activates these proteins through its JAK2 kinase domain.

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Fig. 1: Function of STAT3-JAK2 fusion.
Fig. 2: Targetability of STAT3-JAK2 fusion.

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Acknowledgements

This work was supported by Award Numbers R01 CA177734 (ALF), P30 CA15083 (Mayo Clinic Cancer Center), and P50 CA97274 (University of Iowa/Mayo Clinic Lymphoma SPORE) from the National Cancer Institute; Grant number 6574-19 from the Leukemia & Lymphoma Society; the Department of Laboratory Medicine and Pathology, Mayo Clinic; the Clinomics Program of the Center for Individualized Medicine, Mayo Clinic; and the Predolin Foundation.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Guangzhen Hu, Jessica L. Phillips, Hailey K. Jacobs, Rebecca A. Luchtel, Naoki Oishi, Tanya Hundal, Nada H. Ahmed, Akira Satou & Andrew L. Feldman

  2. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Surendra Dasari

  3. Department of Pathology, University of Yamanashi, Chuo, Yamanashi, Japan

    Naoki Oishi

  4. Department of Clinical Pathology, Suez Canal University, Ismailia, Egypt

    Nada H. Ahmed

  5. Department of Surgical Pathology, Aichi Medical University Hospital, Aichi, Japan

    Akira Satou

  6. Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    Alan L. Epstein

  7. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    N. Nora Bennani & Grzegorz S. Nowakowski

  8. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA

    Grzegorz S. Nowakowski

  9. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    Joseph A. Murray

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Correspondence to Andrew L. Feldman.

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Conflict of interest

GSN has consulted for Celgene, MorphoSys, Bayer, AbbVie, Janssen, Selvita, Karyopharm Therapeutics, and Soreno, and has received research support from Curis, Roche, Celgene, MorphoSys, and NanoString. ALF has received research support from Seattle Genetics. The remaining authors have no competing financial interests to declare.

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Hu, G., Phillips, J.L., Dasari, S. et al. Targetability of STAT3-JAK2 fusions: implications for T-cell lymphoproliferative disorders of the gastrointestinal tract. Leukemia 34, 1467–1471 (2020). https://doi.org/10.1038/s41375-019-0678-3

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