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Activating mutations in human acute megakaryoblastic leukemia.

Abstract
Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. To gain insight into the oncogenic process leading to acute megakaryoblastic leukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders. In a series of human AMKL samples from both Down syndrome and non-Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients. The novel mutations were analyzed using BaF3 cells, showing that JAK3 mutations were activating mutations. Finally, we report a novel constitutively active MPL mutant, MPLT487A, observed in a non-Down syndrome childhood AMKL that induces a myeloproliferative disease in mouse bone marrow transplantation assay.
AuthorsSébastien Malinge, Christine Ragu, Veronique Della-Valle, Didier Pisani, Stefan N Constantinescu, Christelle Perez, Jean-Luc Villeval, Dirk Reinhardt, Judith Landman-Parker, Lucienne Michaux, Nicole Dastugue, André Baruchel, William Vainchenker, Jean-Pierre Bourquin, Virginie Penard-Lacronique, Olivier A Bernard
JournalBlood (Blood) Vol. 112 Issue 10 Pg. 4220-6 (Nov 15 2008) ISSN: 1528-0020 [Electronic] United States
PMID18755984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Neoplasm Proteins
Topics
  • Adult
  • Aged
  • Animals
  • Cell Line, Tumor
  • Child
  • Child, Preschool
  • Down Syndrome (genetics, metabolism)
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Leukemia, Megakaryoblastic, Acute (genetics, metabolism)
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Mutation
  • Neoplasm Proteins (biosynthesis, genetics)
  • Neoplasm Transplantation

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