JAK Pathway inhibition as a novel therapeutic strategy in peripheral t-cell lymphomas with associated inflammation

Abstract: Peripheral T-cell lymphomas (PTCLs) carry a dismal prognosis with high relapse rates and mortality due to the lack of targeted therapies and resistance to classical chemotherapies. Many patients with PTCLs present with an inflammatory phenotype which clinically often bestows a higher burden to the patients than the malignant T-cell expansion. This study aimed to find a therapeutic strategy to target both, the malignant T-cells and the inflammatory phenotype using a previously described mouse model of PTCL-NOS driven by the oncogene ITK-SYK and a human angioimmunoblastic T-cell lymphoma (AITL) xenograft model.
Ruxolitinib is a tyrosine kinase inhibitor targeting JAK1 and JAK2 and is broadly used for the treatment of myeloproliferative neoplasms. Due to frequently observed hyperactivation of JAK/STAT signaling in peripheral T-cell lymphomas as well as in myeloid neoplasias, the effects of Ruxolitinib in the two PTCL models were investigated. Vehicle treated mice carrying the ITK-SYK oncogene developed lethal T-cell lymphomas within 60 days after transplantation with massive weight loss, visible skin infiltrates and inflammation. Ruxolitinib treated mice survived with only mild signs of disease and stable weight during the whole treatment period. Ruxolitinib treatment normalized the distribution of the ITK-SYK+ malignant CD4+ T-cells within the thymus. In addition, a strong decrease of inflammatory cytokines in Ruxolitinib treated mice was observed, and secondary granulocytosis in the peripheral blood as well as granulocytic infiltrates in different organs were reduced. In contrast to Ruxolitinib, Pacritinib, which targets exclusively JAK2, had only minor effects on disease development and prolonged mouse survival for a shorter time period than Ruxolitinib. In addition, only Ruxolitinib but not Pacritinib was able to significantly reduce elevated STAT3 phosphorylation levels in the malignant T-cells. This indicates JAK1 and subsequent activation of STAT3 as the major Ruxolitinib target in malignant transformation which was confirmed by in vitro experiments providing evidence that ITK-SYK expression in a murine CD4+ T-cell line activated JAK1, JAK3, STAT3 and STAT6 but not JAK2, STAT4 and STAT5. This study implicates a positive feedback loop by which the malignant ITK-SYK expressing T-cells activate JAK1/3 STAT3/6 signaling to secrete high amounts of inflammatory IFNγ which in turn activates myeloid cells to secrete IL-6 which then again stimulates further T-cell activation. Ruxolitinib has proven to be a highly effective treatment strategy to interrupt multiple steps of this signaling cascade.
Finally, Ruxolitinib treatment of a human AITL xenograft had the same beneficial effects on disease development by inhibiting proliferation of the primary malignant T-cells and subsequent mobilization and release into the PB as well as the expansion of inflammatory myeloid cells and the secretion of inflammatory cytokines. In conclusion, these data imply JAK1/2 co-inhibitor Ruxolitinib as a promising treatment strategy for different PTCL subtypes

Angaben zum Objekt

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2018

Klassifikation und Themen

• Schlagwort: Inhibition ; Strategy

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2019
• Urheber: Jäger, Amelie
• Beteiligte Personen und Organisationen: Dierks, Christine ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Weitere Informationen

• DOI: 10.6094/UNIFR/17475
• URN: urn:nbn:de:bsz:25-freidok-174759
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:52 MESZ