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.
Highlights
Acute lymphoblastic leukemia (ALL) is a malignant clonal disorder caused by the uncontrolled proliferation of immature lymphoblastic cells in bone marrow, which originate from the abnormal development of hematopoietic stem cells or lymphoid progenitor cells, and may be of B- or T- lymphoid lineage (B-acute lymphoblastic leukemia (ALL) or T-ALL) [1]
All 25 exons of JAK1 were analyzed in these 53 cases using Sanger sequencing, and the P960S mutation was identified in another sample
We studied the effects of JAK1 mutations on human B-ALL NALM-6 cell line, and observed that NALM-6 cells transduced with S646P mutation had an increased percentage of S/G2 phase relative to other groups (Supplementary Figure 1), further confirming the promoting effect on cancer cell proliferation of JAK1 S646P mutation
Summary
Acute lymphoblastic leukemia (ALL) is a malignant clonal disorder caused by the uncontrolled proliferation of immature lymphoblastic cells in bone marrow, which originate from the abnormal development of hematopoietic stem cells or lymphoid progenitor cells, and may be of B- or T- lymphoid lineage (B-ALL or T-ALL) [1]. Given the considerable progress in risk stratification and chemotherapy, the long-term survival rate of childhood ALL has improved to approximately 90% [3]. The overall survival of adult ALL improved to 30–40% after adaptation of pediatric protocols, the prognosis remains poor due to the unsatisfactory response to chemotherapy [4]. BCR-ABL1 is the most common molecular abnormality in adult ALL and associated with poor outcome; by contrast, hyperdiplody and ETV6-RUNX1/TEL-AML1 (both associated with favorable outcome) are more common in childhood ALL, which may be partly responsible for the better outcome in children than that in adults [6]. Current therapies that target specific genetic alterations remain insufficient, except for tyrosine kinase inhibitors (TKIs) such as imatinib in the treatment for BCR-ABL1-positive leukemia [7]. The discovery of novel biological targets and agents is of great interest
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
