Mutant STAT5B in Natural Killer cells- oncogenic driver and therapeutic target in aggressive NK cell malignancies?

The signal transducer and activator of transcription 5B (STAT5B) is a 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 with a poor prognosis. There are no targeted treatment approaches, although there is a mouse model for the T-cell disease driven by STAT5BN642H in which (h)STAT5BN642H (triggered by expression of the gene via the Vav1 promoter) elicits a fatal CD8+ T-cell leukemia. We believe the T-cell disease masks co-existing NK cell malignancies. We now intend to establish a model specific for NK-cell leukemia driven by STAT5BN642H. We have generated transgenic mice in which the expression of hSTAT5BN642H is restricted to the NK-cell lineage and we plan to investigate the ability of STAT5BN642H to act as an oncogenic driver in innate lymphocyte neoplasms. We will analyse NK-cell development, maturation and function and monitor the development of NK-cell leukemia in the mice. If the mutation is not able on its own to trigger an NK-cell malignancy in vivo, we will introduce second hits selected from human data. We will derive mechanistic insights into mutant STAT5B-driven NK cell transformation by a combination of next-generation sequencing approaches. Combining RNA-Seq and ChIP- Seq will reveal hSTAT5BN642H-specific transcriptional alterations that contribute to NK-cell transformation and indicate therapeutic vulnerabilities. To define the common ground for STAT5B–driven NK-cell malignancies we will compare murine and human data using integrative bioinformatics approaches. In summary, the proposed project will provide a novel NK-cell leukemia model and will thereby enable the development of novel treatment options for aggressive NK-cell malignancies.

Zentrum für Biologische Wissenschaften