Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Oncotarget	8	21	2017 May 23	34687-34697	Oncotarget

URL

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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

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 (UniProt.org). 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, Nov 2024).
JAK1	S646P	missense	gain of function	JAK1 S646P lies within the protein kinase domain 1 of the Jak1 protein (UniProt.org). 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