University of Veterinary Medicine Vienna A lineage-specific STAT5BN642H mouse model to study NK-cell leukemia Patients with T- and natural killer (NK)-cell neoplasms frequently have somatic STAT5B gain-of-function mutations. The most frequent STAT5B mutation is STAT5BN642H, which is known to drive murine T-cell leukemia, although its role in NK-cell malignancies is unclear. Introduction of the STAT5BN642H mutation into human NK-cell lines enhances their potential to induce leukemia in mice. We have generated a mouse model that enables tissue-specific expression of STAT5BN642H and have selectively expressed the mutated STAT5B in hematopoietic cells (N642Hvav/+) or exclusively in NK cells (N642HNK/NK). All N642Hvav/+ mice rapidly develop an aggressive T/NKT-cell leukemia, whereas N642HNK/NK mice display an indolent NK-large granular lymphocytic leukemia (NK-LGLL) that progresses to an aggressive leukemia with age. Samples from patients with NK-cell leukemia have a distinctive transcriptional signature driven by mutant STAT5B, which overlaps with that of murine leukemic N642HNK/NK NK cells. To our knowledge, we have generated the first reliable STAT5BN642H-driven preclinical mouse model that displays an indolent NK-LGLL progressing to aggressive NK-cell leukemia. This novel in vivo tool will enable us to explore the transition from an indolent to an aggressive disease and will thus permit the study of prevention and treatment options for NK-cell malignancies. en TEXT journal article Wissenschaftlicher Artikel Articolo di rivista Testo Articolo di rivista Text journal article Text Wissenschaftlicher Artikel Immunobiology And Immunotherapy Lymphoid Neoplasia 2024 2024 Klara Klein Sebastian Kollmann Angela Hiesinger Julia List Jonatan Kendler Thorsten Klampfl Mehak Rhandawa Jana Tri Finopoulos Barbara Maurer Reinhard Grausenburger Christof A. Betram Richard Moriggl Thomas Ruelicke Charles Mullighan Agnieszka Witalisz-Siepracka Wencke Walter Gregor Hoermann Veronika Sexl Dagmar Gotthardt American Society of Hematology