phaidra.vetmeduni.ac.at o:4462 DOI 10.1182/blood.2023022655 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. eng Immunobiology And Immunotherapy Lymphoid Neoplasia 2025-10-20T08:58:53.798Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Klein;Klara; FN:Klara Klein END:VCARD BEGIN:VCARD VERSION:3.0 N:Kollmann;Sebastian; FN:Sebastian Kollmann X-ORCID:https://orcid.org/0000-0001-7911-9896 END:VCARD BEGIN:VCARD VERSION:3.0 N:Hiesinger;Angela; FN:Angela Hiesinger X-ORCID:https://orcid.org/0009-0000-1331-084X END:VCARD BEGIN:VCARD VERSION:3.0 N:List;Julia; FN:Julia List X-ORCID:https://orcid.org/0000-0002-4199-3198 END:VCARD BEGIN:VCARD VERSION:3.0 N:Kendler;Jonatan; FN:Jonatan Kendler X-ORCID:https://orcid.org/0000-0002-2470-4868 END:VCARD BEGIN:VCARD VERSION:3.0 N:Klampfl;Thorsten; FN:Thorsten Klampfl X-ORCID:https://orcid.org/0000-0002-6666-9773 END:VCARD BEGIN:VCARD VERSION:3.0 N:Rhandawa;Mehak; FN:Mehak Rhandawa END:VCARD BEGIN:VCARD VERSION:3.0 N:Finopoulos;Jana Tri; FN:Jana Tri Finopoulos END:VCARD BEGIN:VCARD VERSION:3.0 N:Maurer;Barbara; FN:Barbara Maurer X-ORCID:https://orcid.org/0000-0003-1343-8194 END:VCARD BEGIN:VCARD VERSION:3.0 N:Grausenburger;Reinhard; FN:Reinhard Grausenburger X-ORCID:https://orcid.org/0000-0002-5972-3372 END:VCARD BEGIN:VCARD VERSION:3.0 N:Betram;Christof A.; FN:Christof A. Betram END:VCARD BEGIN:VCARD VERSION:3.0 N:Moriggl;Richard; FN:Richard Moriggl X-ORCID:https://orcid.org/0000-0003-0918-9463 END:VCARD BEGIN:VCARD VERSION:3.0 N:Ruelicke;Thomas; FN:Thomas Ruelicke X-ORCID:https://orcid.org/0000-0002-2121-9496 END:VCARD BEGIN:VCARD VERSION:3.0 N:Mullighan;Charles; FN:Charles Mullighan END:VCARD BEGIN:VCARD VERSION:3.0 N:Witalisz-Siepracka;Agnieszka; FN:Agnieszka Witalisz-Siepracka X-ORCID:https://orcid.org/0000-0003-0237-0745 END:VCARD BEGIN:VCARD VERSION:3.0 N:Walter;Wencke; FN:Wencke Walter END:VCARD BEGIN:VCARD VERSION:3.0 N:Hoermann;Gregor; FN:Gregor Hoermann END:VCARD BEGIN:VCARD VERSION:3.0 N:Sexl;Veronika; FN:Veronika Sexl X-ORCID:https://orcid.org/0000-0001-9363-0412 END:VCARD BEGIN:VCARD VERSION:3.0 N:Gotthardt;Dagmar; FN:Dagmar Gotthardt X-ORCID:https://orcid.org/0000-0002-8416-1236 END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by-nc-nd/4.0 application/pdf 5590419 https://phaidra.vetmeduni.ac.at/o:4462 https://phaidra.vetmeduni.ac.at/api/object/o:4462/thumbnail LOMv1.0 discipline