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Ref Type Journal Article
PMID (28410228)
Authors Li Q, Li B, Hu L, Ning H, Jiang M, Wang D, Liu T, Zhang B, Chen H
Title Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia.
Journal Oncotarget
Vol 8
Issue 21
Date 2017 May 23
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK1 N973K missense unknown JAK1 N973K lies within protein kinase domain 2 of the Jak1 protein ( N973K has been identified in the scientific literature (PMID: 28410228), but has not been biochemically characterized and therefore, its effect on Jak1 protein function is unknown (PubMed, May 2022).
JAK1 S646P missense gain of function JAK1 S646P lies within the protein kinase domain 1 of the Jak1 protein ( S646P results in autophosphorylation of Jak1, constitutive activation of Stat3 and Erk, and is transforming in culture (PMID: 28410228).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK1 S646P Advanced Solid Tumor sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, treatment with Jakafi (ruxolitinib) resulted in inhibition of both Jak1 autophosphorylation and Stat3 and Erk activity, and inhibition of cell proliferation in culture in transformed cells expressing JAK1 S646P (PMID: 28410228). 28410228