Degradation of Janus kinases in CRLF2-rearranged acute lymphoblastic leukemia

CRLF2-rearranged acute lymphoblastic leukemia (ALL) comprises over half of Philadelphia chromosome-like (Ph-like) ALL, is associated with poor outcome in children and adults, and lacks effective therapy. Overexpression of CRLF2 results in activation of JAK-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of Janus kinases show limited efficacy. Here we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against Janus kinases in in vitro and in in vivo. The resulting JAK PROTACs were evaluated for target degradation by proteomic approaches, and activity tested in CRLF2 rearranged cell line and xenograft models of ALL.