Reference Detail

Ref Type

Journal Article

PMID

(29025600)

Authors

Sadras T, Heatley SL, Kok CH, McClure BJ, Yeung D, Hughes TP, Sutton R, Ziegler DS, White DL

Title

A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOH.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer genetics	216-217		2017 Oct	86-90	Cancer Genet

URL

Abstract Text

We report a novel somatic mutation in the kinase domain of JAK2 (R938Q) in a high-risk pediatric case of B-cell acute lymphoblastic leukemia (ALL). The patient developed on-therapy relapse at 12 months, and interestingly, the JAK2 locus acquired loss of heterozygosity during treatment resulting in 100% mutation load. Furthermore, we show that primary ALL mononuclear cells harboring the JAK2 R938Q mutation display reduced sensitivity to the JAK1/2 ATP-competitive inhibitor ruxolitinib in vitro, compared to ALL cells that carry a more common JAK2 pseudokinase domain mutation. Our findings are in line with previous reports that demonstrate that mutations within the kinase domain of JAK2 are associated with resistance to type I JAK inhibitors. Importantly, given the recent inclusion of ruxolitinib in trial protocols for children with JAK pathway alterations, we predict that inter-patient genetic variability may result in suboptimal responses to JAK inhibitor therapy in a subset of cases. The need for alternate targeted and/or combination therapies for patients who display inherent or developed resistance to JAK inhibitor therapy will be warranted, and we propose that kinase-mutants less sensitive to type I JAK inhibitors may present a currently unexplored platform for investigation of improved therapies.

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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
JAK2	R938Q	missense	gain of function	JAK2 R938Q lies within the protein kinase domain 2 of the Jak2 protein (UniProt.org). R938Q confers a gain of function to the Jak2 protein, as demonstrated by constitutive Stat5 signaling (PMID: 29025600), transformation of cultured cells (PMID: 24398328), and also displays resistance to Jak1/2 ATP-competitive inhibitors (PMID: 29025600).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK2 R938Q	childhood B-cell acute lymphoblastic leukemia	resistant	Ruxolitinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, bone marrow mononuclear cells from a pediatric B-cell acute lymphoblastic leukemia with an acquired Jak2 R938Q mutation were resistant to Jakafi (ruxolitinib) (PMID: 29025600).	29025600