Correlation Engine 2.0
Clear Search sequence regions

  • b cell (1)
  • base sequence (1)
  • cell (3)
  • child (1)
  • children (1)
  • female (1)
  • gene (1)
  • humans (1)
  • JAK (5)
  • JAK1 (1)
  • JAK2 (6)
  • jak2 protein, human (1)
  • Janus (2)
  • leukemia (5)
  • patient (3)
  • protein domains (1)
  • protein human (1)
  • rapid (1)
  • ruxolitinib (2)
  • therapies (2)
  • vitro (1)
  • Sizes of these terms reflect their relevance to your search.

    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. Copyright © 2017. Published by Elsevier Inc.


    Teresa Sadras, Susan L Heatley, Chung H Kok, Barbara J McClure, David Yeung, Timothy P Hughes, Rosemary Sutton, David S Ziegler, Deborah L White. A novel somatic JAK2 kinase-domain mutation in pediatric acute lymphoblastic leukemia with rapid on-treatment development of LOH. Cancer genetics. 2017 Oct;216-217:86-90

    Expand section icon Mesh Tags

    Expand section icon Substances

    PMID: 29025600

    View Full Text