Abstract 2752: The gain-of-function STAT5BN642H mutation as a driver of mature T cell leukemia/lymphoma
Authors: Heidi A. Neubauer, Tobias Suske, Susann Schönefeldt, Simone Tangermann, Auke Boersma, Thomas Rülicke, Vasileios Bekiaris, Lukas Kenner, Richard Moriggl
Journal: Cancer Research (2020)

Abstract Mature T cell leukemias/lymphomas (MaTCL) are a group of rare hematological malignancies of mostly incurable prospects due to limited efficient therapies and a lack of faithful pre-clinical models. STAT5 transcription factors are critical downstream effectors of cytokine and growth factor signaling through the JAK/STAT pathway, particularly in the hematopoietic compartment. The two gene products, STAT5A and STAT5B, play important roles in cell proliferation, survival and differentiation. It is increasingly evident that hyperactive JAK/STAT signaling plays a role in these MaTCL diseases. Notably, a hotspot gain-of-function (GOF) mutation in STAT5B, N642H, has been found in over 100 patients with T cell neoplasia, and is associated with more aggressive disease, therapy resistance and worse prognosis. To investigate the role of STAT5BN642H in MaTCL, we utilized our transgenic mouse model harboring moderate expression of human STAT5BN642H in the hematopoietic compartment. Notably, STAT5BN642H transgenic mice rapidly develop aggressive mature CD8+ T cell disease, suggesting that CD8+ T cells are particularly susceptible to transformation by this mutation. Further examination of these mice revealed prominent infiltration of neoplastic T cells into peripheral organs including lung, skin, brain and liver. Interestingly, in addition to CD8+ T cells, infiltration of CD4+ as well as γδ T cells was also observed in various organs of the STAT5BN642H mice, suggestive of STAT5BN642H-driven transformation of other T cell lineages. This would be more consistent with human patients carrying this mutation, who suffer predominantly from MaTCL of CD4+ or aggressive γδ T cell subtypes. Therefore, we isolated these T cell subsets from the transgenic mice and performed syngeneic transplant experiments to assess T cell transformation. Indeed, transplants of γδ or CD4+ T cells from STAT5BN642H transgenic mice into immunocompetent recipients resulted in the development of γδ or CD4+ T cell neoplasia, respectively, demonstrating the full transforming capacity of STAT5BN642H in multiple T cell lineages. From this, we have generated a novel γδ T cell line harboring the STAT5BN642H mutation, which we are utilizing together with the mouse models to interrogate oncogenic mechanisms of STAT5B (through immunophenotyping and sequencing efforts) as well as to screen and test new therapeutic options for these diseases. Overall, these data highlight the aggressive nature of the STAT5BN642H driver mutation in MaTCL. We report on novel pre-clinical models for aggressive γδ or CD4+ MaTCL that more closely recapitulate human disease. These models will be valuable for understanding STAT5BN642H-driven T cell disease and for testing new, urgently needed MaTCL treatment strategies. Citation Format: Heidi A. Neubauer, Tobias Suske, Susann Schönefeldt, Simone Tangermann, Auke Boersma, Thomas Rülicke, Vasileios Bekiaris, Lukas Kenner, Richard Moriggl. The gain-of-function STAT5BN642H mutation as a driver of mature T cell leukemia/lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2752.