Inhibiting Janus Kinase 1 and BCL-2 to treat T cell acute lymphoblastic leukemia with IL7-Rα mutations

// Emilee Senkevitch 1 , Wenqing Li 1 , Julie A. Hixon 1 , Caroline Andrews 1, 2, 3 , Sarah D. Cramer 1, 2, 4 , Gary T. Pauly 6 , Timothy Back 1 , Kelli Czarra 5 and Scott K. Durum 1 1 Cytokines and Immunity Section, Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA 2 Comparative Biomedical Scientist Training Program, NIH, Bethesda, MD, USA 3 Michigan State University, East Lansing, MI, USA 4 Department of Veterinary Medicine, University of Maryland, College Park, MD, USA 5 Laboratory Animal Sciences Program, Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA 6 Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD, USA Correspondence to: Scott K. Durum, email: durums@mail.nih.gov Keywords: JAK1; BCL-2; T-ALL; ruxolitinib; venetoclax Received: June 23, 2017      Accepted: April 04, 2018      Published: April 27, 2018 ABSTRACT 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.