Somatic STAT5BN642H Mutations: From Hematopoietic Origins to Pleiotropic Disease Manifestations

• Applicants: Dr. Branko Cirovic; Professor Dr. Stephan Ehl
• Subject Area: Hematology, Oncology ; Immunology ; Clinical Immunology and Allergology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569178986

In the context of hematological diseases, acquisition of somatic mutations is commonly associated with malignant transformation and cancer. However, in an increasing number of genes, the identical somatic mutations have also been associated with non-malignant immune-related phenotypes, including lymphoproliferation, inflammation, autoimmunity and allergy. This emerging research field calls for comprehensive research approaches and precise model systems to better understand the mechanisms determining the clinical outcome of somatic mutations. One such example is the N642H variant in the transcription factor STAT5B. This variant confers a gain-of-function effect leading to amplified JAK/STAT pathway activity. Initially identified in T/NK-cell malignancies and hypereosinophilic syndromes, somatic STAT5BN642H mutations were recently found in pediatric patients with variable immune-associated disorders mimicking inborn errors of immunity, but without malignancy. STAT5BN642H mutational patterns varied among patients and across different cell subsets, suggesting that disease manifestations are cell-type specific and affected by the mutation’s origin in distinct multipotent progenitor cells. The central hypothesis of this project is that both the nature of the initial cell acquiring the STAT5BN642H mutation and external factors enhancing its gain-of-function effect determine the resulting disease phenotype. To address this hypothesis, we will integrate analyses from patients and results from a new mouse model. This system enables both precise activation of STAT5BN642H in situ and high-resolution clonal lineage tracing using PolyloxExpress cellular barcoding. Our project covers four major aspects: (1) characterizing the mutational burden and the functional consequences of STAT5BN642H in T/NK cells, eosinophils and progenitors using patient-derived material, (2) defining the impact of precise STAT5BN642H induction in specific hematopoietic progenitor subsets or NK cells on clonal evolution and disease development, (3) investigating viral infections (LCMV/MCMV) as external modulators of cell type-specific disease progression and (4) evaluating pharmacological intervention (Rapamycin/Ruxolitinib) to mitigate STAT5BN642H-driven disease. The project uses the complementary assets of the research partners by integrating patient analysis with mechanistic in vivo modeling including state-of-the art in situ cell barcoding technologies and viral infections. Thereby we will provide a more complete understanding of how a single somatic variant can lead to a spectrum of immune-mediated disorders and cancers. This multifaceted approach has the potential to yield valuable insights into the pathophysiology of genetically disturbed hematopoiesis and inform the development of targeted therapies for affected patients.

• DFG Programme: Research Grants
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Cooperation Partner: Professorin Dr. Dagmar Gotthardt