Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations
| Autor: | Caroline Andrews, Timothy C. Back, Sarah D. Cramer, Gary T. Pauly, Julie A. Hixon, Emilee Senkevitch, Kelli Czarra, Scott K. Durum, Wenqing Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Ruxolitinib ruxolitinib T cell BCL-2 03 medical and health sciences chemistry.chemical_compound Medicine Janus kinase 1 venetoclax business.industry Venetoclax Cancer medicine.disease Thymocyte Leukemia 030104 developmental biology medicine.anatomical_structure JAK1 Oncology chemistry Cancer research business T-ALL medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current chemotherapy is quite toxic in growing children and more directed therapeutics are being sought. The IL-7R pathway is a major driver of ALL and here we evaluate two drugs directed to that pathway using a model of T cell ALL. Mutant gain-of-function IL-7Rα was transduced into an IL-7-dependent murine thymocyte line conferring ligand-independent survival and growth. JAK1 is associated with IL-7Rα and mediates signaling from the mutant receptor. In vitro, treating the transformed cell line with the JAK1/2 inhibitor ruxolitinib inhibited ligand-independent signaling and induced cell death. Transfer of the transformed cell line into mice resulted in aggressive leukemia and untreated mice succumbed in about three weeks. Treatment with ruxolitinib incorporated into chow showed a potent therapeutic benefit with reduction in leukemic burden and extension of survival. BCL-2 is an anti-apoptotic downstream mediator of the IL-7R survival mechanism. Venetoclax, an inhibitor of BCL-2, showed activity against the transformed cell line in vitro and could be combined with ruxolitinib in vivo. These findings support the therapeutic potential of treating T-ALL by targeting the IL-7R pathway. |
| Databáze: | OpenAIRE |
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