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|Ref Type||Journal Article|
|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.|
|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.|
|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|
|Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|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||B-cell childhood 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|