title: Novel activating JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic leukemia.
abstract: Activation of tyrosine kinase genes is a frequent event in human hematologic malignancies. Because gene activation could be associated with gene dysregulation, we attempted to screen for activating gene mutation based on high-level gene expression. We focused our study on the Janus kinase 2 (JAK2) gene in 90 cases of acute leukemia. This strategy led to the identification of a novel JAK2-acquired mutation in a patient with Down syndrome (DS) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This mutation involves a 5-amino acid deletion within the JH2 pseudokinase domain (JAK2DeltaIREED). Expression of JAK2DeltaIREED in Ba/F3 cells induced constitutive activation of the JAK-STAT pathway and growth factor-independent cell proliferation. These results highlight the JAK2 pseudokinase domain as an oncogenic hot spot and indicate that activation of the JAK-STAT pathway may contribute to lymphoid malignancies and hematologic disorders observed in children with DS.
authors.affiliation: Institut National de la Santé et de la Recherche Scientifique (INSERM), E0210, Paris, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Malinge
authors.forename: Raouf
authors.initials: R
authors.lastname: Ben-Abdelali
authors.forename: Catherine
authors.initials: C
authors.lastname: Settegrana
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford-Weiss
authors.forename: Marianne
authors.initials: M
authors.lastname: Debre
authors.forename: Kheira
authors.initials: K
authors.lastname: Beldjord
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Macintyre
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Villeval
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Roland
authors.initials: R
authors.lastname: Berger
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.forename: Virginie
authors.initials: V
authors.lastname: Penard-Lacronique
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D001483:Base Sequence; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002675:Child, Preschool; D017124:Conserved Sequence; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016415:Sequence Alignment
chemical_list: D053614:Janus Kinase 2