Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome

Br J Haematol. 2007 May;137(4):337-41. doi: 10.1111/j.1365-2141.2007.06574.x.

Abstract

Acquired mutations activating Janus kinase 3 (jak3) have been reported in Down syndrome (DS) and non-DS patients with acute megakaryoblastic leukaemia (AMKL). This highlighted jak3-activation as an important event in the pathogenesis of AMKL, and predicted inhibitors of jak3 as conceptual therapeutics for AMKL. Of 16 DS-transient myeloproliferative disorder (TMD)/AMKL patients tested, seven showed JAK3 mutations. Three mutations deleted the kinase (JH1) domain, abolishing the main function of jak3. Another patient displayed a mutation identical to a previously reported inherited loss-of-function causing severe combined immunodeficiency. Our data suggest that both gain-, and loss-of function mutations of jak3 can be acquired in DS-TMD/AMKL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Down Syndrome / genetics*
  • Down Syndrome / immunology
  • Enzyme Activation
  • Gene Deletion
  • Humans
  • Janus Kinase 3 / genetics*
  • Leukemia, Megakaryoblastic, Acute / complications
  • Leukemia, Megakaryoblastic, Acute / genetics*
  • Molecular Sequence Data
  • Mutation*
  • Protein-Tyrosine Kinases / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA

Substances

  • Protein-Tyrosine Kinases
  • Janus Kinase 3

Grants and funding