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.

CRLF2重排急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）占费城染色体样（Philadelphia chromosome-like, Ph-like）ALL的半数以上，与儿童及成人患者的不良预后密切相关，且目前尚无有效治疗手段。实验模型研究显示，CRLF2过表达可激活贾纳斯激酶-信号转导与转录激活因子（JAK-STAT）信号通路及平行信号通路，但现有贾纳斯激酶（Janus kinases, JAK）小分子抑制剂的疗效有限。本研究评估了靶向贾纳斯激酶的蛋白水解靶向嵌合体（proteolysis-targeting chimeras, PROTACs）在体外及体内的抗肿瘤活性。通过蛋白质组学方法对所得JAK靶向PROTAC的靶蛋白降解情况进行了评估，并在CRLF2重排的ALL细胞系及异种移植模型中验证了其活性。