A lineage-specificSTAT5BN642Hmouse model to study NK-cell leukemia

Abstract

AbstractPatients with T- and NK-cell neoplasms frequently have somaticSTAT5Bgain-of-function mutations. The most frequentSTAT5Bmutation isSTAT5BN642H, which is known to drive murine T-cell leukemia although its role in NK-cell malignancies is unclear.Introduction of theSTAT5BN642Hmutation into human NK-cell lines enhances their potential to induce leukemia in mice. We have generated a mouse model that enables tissue-specific expression ofSTAT5BN642Hand have selectively expressed the mutatedSTAT5Bin hematopoietic cells (N642Hvav/+) or exclusively in NK cells (N642HNK/NK). All N642Hvav/+mice rapidly develop an aggressive T-/NK T-cell leukemia, whereas N642HNK/NKmice display an indolent chronic lymphoproliferative disorder of NK cells (CLPD-NK) that progresses to an aggressive leukemia with age. Samples from NK-cell leukemia patients have a distinctive transcriptional signature driven by mutant STAT5B, which overlaps with that of murineSTAT5BN642H-expressing NK cells.We have generated the first reliableSTAT5BN642H-driven pre-clinical mouse model that displays an indolent CLPD-NK progressing to aggressive NK-cell leukemia. This novelin vivotool 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.Key pointsGeneration of a lineage-specificSTAT5BN642Htransgenic mouse model which develops NK-cell leukemiaLeukemic NK cells with a STAT5B gain of function mutation have a unique transcriptional profile in mice and human patients