https://phaidra.vetmeduni.ac.at/o:4462 A lineage-specific STAT5BN642H mouse model to study NK-cell leukemia Klein, Klara Klara Klein Kollmann, Sebastian Sebastian Kollmann 0000-0001-7911-9896 University of Veterinary Medicine Vienna Hiesinger, Angela Angela Hiesinger 0009-0000-1331-084X University of Veterinary Medicine Vienna List, Julia Julia List 0000-0002-4199-3198 University of Veterinary Medicine Vienna Kendler, Jonatan Jonatan Kendler 0000-0002-2470-4868 University of Veterinary Medicine Vienna Klampfl, Thorsten Thorsten Klampfl 0000-0002-6666-9773 University of Veterinary Medicine Vienna Rhandawa, Mehak Mehak Rhandawa Finopoulos, Jana Tri Jana Tri Finopoulos Maurer, Barbara Barbara Maurer 0000-0003-1343-8194 University of Veterinary Medicine Vienna Grausenburger, Reinhard Reinhard Grausenburger 0000-0002-5972-3372 University of Veterinary Medicine Vienna Betram, Christof A. Christof A. Betram University of Veterinary Medicine Vienna Moriggl, Richard Richard Moriggl 0000-0003-0918-9463 University of Veterinary Medicine Vienna Ruelicke, Thomas Thomas Ruelicke 0000-0002-2121-9496 University of Veterinary Medicine Vienna Mullighan, Charles Charles Mullighan Witalisz-Siepracka, Agnieszka Agnieszka Witalisz-Siepracka 0000-0003-0237-0745 University of Veterinary Medicine Vienna Walter, Wencke Wencke Walter Hoermann, Gregor Gregor Hoermann Sexl, Veronika Veronika Sexl 0000-0001-9363-0412 University of Veterinary Medicine Vienna Gotthardt, Dagmar Dagmar Gotthardt 0000-0002-8416-1236 University of Veterinary Medicine Vienna American Society of Hematology journal article open access eng 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. Immunobiology And Immunotherapy Lymphoid Neoplasia http://creativecommons.org/licenses/by-nc-nd/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4462/download 10.1182/blood.2023022655 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Blood issn:1528-0020 VoR Blood 143 24 5.33 MB 2024