Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia

// Qian Li 1, 2, * , Botao Li 1, 2, * , Liangding Hu 1 , Hongmei Ning 1 , Min Jiang 1 , Danhong Wang 1, 2 , Tingting Liu 1 , Bin Zhang 1, 2 , Hu Chen 1, 2 1 Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of the Academy of Military Medical Sciences, Beijing, China 2 Cell and Gene Therapy Center, Affiliated Hospital of the Academy of Military Medical Sciences, Beijing, China * These authors contributed equally to this work Correspondence to: Hu Chen, email: chenhu217@aliyun.com Bin Zhang, email: zb307ctc@163.com Keywords: acute lymphoblastic leukemia, whole-exome sequencing, mutation, JAK1, ruxolitinib Received: July 10, 2016      Accepted: March 17, 2017      Published: March 29, 2017 ABSTRACT The survival rate of childhood acute lymphoblastic leukemia (ALL) is approaching 90%, while the prognosis of adults remains poor due to the limited therapeutic approaches. In order to identify new targets for ALL, we performed whole-exome sequencing on four adults with B-ALL and discovered a somatic JAK1 S646P mutation. Sanger sequencing of JAK1 was conducted on 53 ALL patients, and two cases exhibited A639G and P960S mutations separately. Functional studies demonstrated that only JAK1 S646P mutation could activate multiple signaling pathways, drive cytokine-independent cell growth, and promote proliferation of malignant cells in nude mice. Moreover, a high sensitivity to the JAK1/2 inhibitor ruxolitinib was observed in S646P mutant model. Exploration in a total of 209 ALL cases showed that JAK1 mutations occur at a frequency of 10.5% in T-ALL (2/19) and 1.6% in B-ALL (3/190). Collectively, our results suggested that JAK1 S646P is an activating mutation in vitro and in vivo . JAK-STAT pathway might represent a promising therapeutic target for ALL.