Oncogenic mechanisms of mutant STAT5B in natural killer cells

The signal transducer and activator of transcription 5B (STAT5B) is a master regulator of development, survival and function of innate and innate-like lymphocytes, including natural killer (NK) and NKT cells. The gain-of-function mutation N642H in the SH2 domain of human STAT5B is associated with aggressive forms of CD56-positive T (NKT) and NK cell lymphomas/leukemias. We will investigate the ability of STAT5BN642H to act as an oncogenic driver in innate lymphocyte neoplasms. A mouse model expressing human (h)STAT5BN642H in all hematopoietic cells under the Vav1 promoter develops a severe CD8+ T cell neoplasia but we did not observe NK cell malignancies. We believe that they are masked by the T cell disease. To test this idea, we will generate a novel mouse model in which expression of hSTAT5BN642H is restricted to the NK cell lineage, thereby avoiding competition with more potently transformed cell types. We will measure the effects of mutant STAT5B on NK cell development, maturation and function. We will monitor mice for the development of mutant STAT5B-driven NK cell leukemias, which will be characterized in detail. Mechanistic insights into mutant STAT5B-driven NK cell transformation will be gained by high-throughput analysis, which will uncover hSTAT5BN642H-specific transcriptional alterations and thereby give indications of potential therapeutic vulnerabilities. Our project will establish a novel hSTAT5BN642H-driven NK cell leukemia model that will enable the development of treatment options for aggressive NK cell malignancies that are currently untreatable.

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Zentrum für Biologische Wissenschaften