Veterinärmedizinische Universität Wien Forschungsinformationssystem VetDoc

Grafischer Link zur Startseite der Vetmeduni Vienna

Gewählte Publikation:

Open Access Logo

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2018

AutorInnen: Pham, HTT; Maurer, B; Prchal-Murphy, M; Grausenburger, R; Grundschober, E; Javaheri, T; Nivarthi, H; Boersma, A; Kolbe, T; Elabd, M; Halbritter, F; Pencik, J; Kazemi, Z; Grebien, F; Hengstschläger, M; Kenner, L; Kubicek, S; Farlik, M; Bock, C; Valent, P; Müller, M; Rülicke, T; Sexl, V; Moriggl, R

Titel: STAT5BN642H is a driver mutation for T cell neoplasia.

Quelle: J Clin Invest. 2018; 128(1):387-401



Autor/innen der Vetmeduni Vienna:

Boersma Auke
Grebien Florian
Grundschober Eva
Javaheri Tahereh
Kenner Lukas
Kolbe Thomas
Maurer Barbara
Moriggl Richard
Pham Ha
Prchal-Murphy Michaela
Rülicke Thomas
Sexl Veronika

Beteiligte Vetmed-Organisationseinheiten
Institut für Tierzucht und Genetik, Abteilung für Funktionelle Krebsgenomik
Institut für Pathologie, Abteilung für Labortierpathologie
Institut für In-vivo und In-vitro-Modelle
Institut für Pharmakologie und Toxikologie
Plattform Biomodels Austria


Zugehörige(s) Projekt(e): Targeting STAT5 regulierte Transkription in myeloproliferativen Neoplasien


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

Keywords Pubmed: Amino Acid Substitution
Animals
CD8-Positive T-Lymphocytesmetabolismpathology
DNA Methylationgenetics
DNA, Neoplasmgeneticsmetabolism
Hematologic Neoplasmsgeneticsmetabolism
Humans
Leukemia, T-Cellgeneticsmetabolismpathology
Lymphoma, T-Cellgeneticsmetabolismpathology
Mice
Mice, Transgenic
Mutation, Missense
Neoplasm Proteinsgeneticsmetabolism
STAT5 Transcription Factorgeneticsmetabolism

© Veterinärmedizinische Universität Wien Hilfe und DownloadsErklärung zur Barrierefreiheit