Recurrent mutation of <i>JAK3</i> in T‐cell prolymphocytic leukemia

  • Anke K. Bergmann
    Institute for Human Genetics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  • Sina Schneppenheim
    Institute for Human Genetics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  • Marc Seifert
    Institute of Cell Biology (Cancer Research) Medical School Essen, University of Duisburg‐Essen Essen Germany
  • Matthew J. Betts
    Cell Networks Excellenz Cluster Bioquant, University of Heidelberg Heidelberg Germany
  • Andrea Haake
    Institute for Human Genetics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  • Cristina Lopez
    Institute for Human Genetics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  • Eva Maria Murga Penas
    Institute for Human Genetics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  • Inga Vater
    Institute for Human Genetics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  • Sandrine Jayne
    The MRC Toxicology Unit University of Leicester Leicester UK
  • Martin J.S. Dyer
    The MRC Toxicology Unit University of Leicester Leicester UK
  • Martin Schrappe
    Department of Pediatrics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  • Ulrich Dührsen
    Department of Hematology University Hospital Essen, University of Duisburg‐Essen Essen Germany
  • Ole Ammerpohl
    Institute for Human Genetics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany
  • Robert B. Russell
    Cell Networks Excellenz Cluster Bioquant, University of Heidelberg Heidelberg Germany
  • Ralf Küppers
    Institute of Cell Biology (Cancer Research) Medical School Essen, University of Duisburg‐Essen Essen Germany
  • Jan Dürig
    Department of Hematology University Hospital Essen, University of Duisburg‐Essen Essen Germany
  • Reiner Siebert
    Institute for Human Genetics Christian‐Albrechts‐University Kiel and University Hospital Schleswig‐Holstein Campus Kiel Kiel Germany

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説明

<jats:p>T‐cell prolymphocytic leukemia (T‐PLL) is an aggressive post‐thymic T‐cell malignancy characterized by the recurrent inv(14)(q11q32)/t(14;14)(q11;q32) or t(X;14)(q28;q11) leading to activation of either the <jats:italic>TCL1</jats:italic> or <jats:italic>MTCP1</jats:italic> gene, respectively. However, these primary genetic events are insufficient to drive leukemogenesis. Recently, activating mutations in <jats:italic>JAK3</jats:italic> have been identified in other T‐cell malignancies. Since JAK3 is essential for T‐cell maturation, we analyzed a cohort of 32 T‐PLL patients for mutational hot spots in the <jats:italic>JAK3</jats:italic> gene using a step‐wise screening approach. We identified 14 mutations in 11 of 32 patients (34%). The most frequently detected mutation in our cohort was M511I (seen in 57% of cases) previously described as an activating change in other T‐cell malignancies. Three patients carried two mutations in <jats:italic>JAK3</jats:italic>. In two patients M511I and R657Q were simultaneously detected and in another patient V674F and V678L. In the latter case we could demonstrate that the mutations were on the same allele in cis. Protein modeling and homology analyses of mutations present in other members of the JAK family suggested that these mutations likely activate JAK3, possibly by disrupting the activation loop and the interface between N and C lobes, increasing the accessibility of the catalytic loop. In addition, four of the 21 patients lacking a <jats:italic>JAK3</jats:italic> point mutation presented an aberrant karyotype involving the chromosomal band 19p13 harboring the <jats:italic>JAK3</jats:italic> locus. The finding of recurrent activating <jats:italic>JAK3</jats:italic> mutations in patients with T‐PLL could enable the use of JAK3 inhibitors to treat patients with this unfavorable malignancy who otherwise have a very poor prognosis. © 2014 Wiley Periodicals, Inc.</jats:p>

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