STAT5BN642H is a driver mutation for T cell neoplasia

• DOI: 10.1172/jci94509
• Publication Date: 2017-12-03T23:00:29Z
• Authors: Ha Thi Thanh Pham; Barbara Maurer; Michaela Prchal-M...; Reinhard Grausenb...; Eva Grundschober; Tahereh Javaheri; Harini Nivarthi; Auke Boersma; Thomas Kolbe; Mohamed Elabd; Florian Halbritter; Jan Pencik; Zahra Kazemi; Florian Grebien; Markus Hengstschl...; Lukas Kenner; Stefan Kubicek; Matthias Farlik; Christoph Bock; Peter Valent; Mathias Müller; Thomas Rülicke; Veronika Sexl; Richard Moriggl
• Keywords: 0303 health sciences; Leukemia, T-Cell; Mutation, Missense; Mice, Transgenic; DNA, Neoplasm; CD8-Positive T-Lymphocytes; DNA Methylation; Lymphoma, T-Cell; Neoplasm Proteins; 3. Good health; Mice; 03 medical and health sciences; Amino Acid Substitution; Hematologic Neoplasms; STAT5 Transcription Factor; Animals; Humans; Research Article

STAT5B is often mutated in hematopoietic malignancies. The most frequent mutation, Asp642His (N642H), has been found over 90 leukemia and lymphoma patients. Here, we used the Vav1 promoter to generate transgenic mouse models that expressed either human or STAT5BN642H compartment. While STAT5B-expressing mice lacked a phenotype, STAT5BN642H-expressing rapidly developed T cell neoplasms. Neoplasia manifested as transplantable CD8+ leukemia, indicating mutation drives cancer development. Persistent enhanced levels of tyrosine phosphorylation transformed cells led profound changes gene expression were accompanied by alterations DNA methylation at potential histone methyltransferase EZH2-binding sites. Aurora kinase genes enriched cells, which exquisitely sensitive JAK inhibitors. Together, our data suggest inhibitors should be further explored therapeutics for patients with who respond poorly conventional chemotherapy.