A lineage-speci fi c STAT5B^N642H mouse model to study NK-cell leukemia

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Trifinopoulos, Jana; Klampfl, Thorsten; List, Julia; Kendler, Jonatan; Bertram, Christof Albert; Gotthardt-Pötsch, Dagmar; Klein-Eberl, Klara; Sexl, Veronika; Kollmann, Sebastian; Hiesinger, Angela

Abstrakt

Patients with T- and natural killer (NK)-cell neoplasms frequently have somatic STAT5B gain -of -function mutations. The most frequent STAT5B mutation is STAT5B N642H , which is known to drive murine T -cell leukemia, although its role in NK-cell malignancies is unclear. Introduction of the STAT5B N642H mutation into human NK-cell lines enhances their potential to induce leukemia in mice. We have generated a mouse model that enables tissue -speci fi c expression of STAT5B N642H and have selectively expressed the mutated STAT5B in hematopoietic cells (N642H vav/+ ) or exclusively in NK cells (N642H NK/NK ). All N642H vav/+ mice rapidly develop an aggressive T/NKT-cell leukemia, whereas N642H NK/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 N642H NK/NK NK cells. To our knowledge, we have generated the fi rst reliable STAT5B N642H -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.

Dokumententyp

Originalarbeit

Open Access Type

Hybrid

DOI

10.1182/blood.2023022655

PubMed ID

MEDLINE:38498036

Projekt

Molecular and Cellular Control of Tissue Homeostasis in Health and Disease