Exploring the role of senescence in the malignant transformation of NK cells

Natural Killer (NK) cell leukemias are relatively rare but aggressive diseases with poor prognosis and limited treatment options, hence representing an unmet clinical need. They frequently feature gain-of-function (GOF) mutations of the JAK/STAT pathway. STAT5BN642H is the most prevalent STAT5 mutation and has been detected in cases of NK-cell leukemia but its exact role in pathogenesis is unknown. To test whether STAT5BN642H is an oncogenic driver in NK cells, we 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-/NK T-cell leukemia, whereas N642HNK/NK mice display an indolent NK-large granular lymphocytic leukemia (NK-LGLL) that progresses to an aggressive leukemia with age in 30% of the mice. The analysis of samples derived from NK-cell leukemia patients revealed a distinctive transcriptional signature driven by mutant STAT5B.The incomplete penetrance of an aggressive NK-cell leukemia in N642HNK/NK mice, and the lack of leukemia of NK-cell origin in N642Hvav/+ mice, indicates an increased barrier for transformation driven by STAT5B-N642H in NK cells. Our working hypothesis is that NK-cell senescence induced by mutant STAT5B may act as a barrier to malignant transformation, which can happen only through the acquisition of specific additional mutations. To test this hypothesis, we will investigate how mutant STAT5B drives NK-cell senescence and how it impacts on the ontogeny of NK-cell malignancies. In addition, we will use established NK-cell lines and our mouse model to study potential prevention and treatment options.

Zentrum für Biologische Wissenschaften