title: Description of a novel Janus kinase 3 P132A mutation in acute megakaryoblastic leukemia and demonstration of previously reported Janus kinase 3 mutations in normal subjects.
abstract: Gain-of-function (GOF) mutations of Janus kinase 2 (JAK2) are frequently seen in myeloproliferative disorders (MPDs). Meanwhile, JAK3 activating substitutions have been found in a few megakaryocytic cell lines and in primary myeloid leukemia (AMKL). Here, we sought to discover novel leukemogenetic mutations in de novo acute myeloid leukemia of non-Down syndrome (N-DS) by DNA sequencing. A total of 191 normal Caucasian individuals were studied to define single nucleotide polymorphisms (SNPs) within the JH2 and JH6 domains. Although known activating substitutions were observed in rare cases of acute myeloid leukemia (AML) (V722I [2/134] or P132T [1/119]), all samples were wild-type (WT) for the oncogenic A572V (119/119). Interestingly, a novel homozygous mutation (P132A) was discovered in a patient with acute megakaryoblastic leukemia and in vivo studies demonstrated that its ectopic expression was oncogenic in a mouse xenotransplant model. This study defines a novel JAK3 mutation among patients with N-DS AML and demonstrates that normal individuals can also display germline JAK3 substitutions, previously proven to have oncogenic properties, in vitro and in vivo. The discovery of these substitutions in normal donors encourages future studies to define new risk factors among patients with MPDs.
authors: Center for Experimental Research and Medical Studies, University of Turin, Turin, Italy.
authors: Ludovica
authors: L
authors: Riera
authors: Elena
authors: E
authors: Lasorsa
authors: Lisa
authors: L
authors: Bonello
authors: Francesca
authors: F
authors: Sismondi
authors: Fabrizio
authors: F
authors: Tondat
authors: Cristiana
authors: C
authors: Di Bello
authors: Paola Francia
authors: PF
authors: Di Celle
authors: Roberto
authors: R
authors: Chiarle
authors: Laura
authors: L
authors: Godio
authors: Achille
authors: A
authors: Pich
authors: Fabio
authors: F
authors: Facchetti
authors: Maurilio
authors: M
authors: Ponzoni
authors: Filippo
authors: F
authors: Marmont
authors: Carlo
authors: C
authors: Zanon
authors: Alberto
authors: A
authors: Bardelli
authors: Giorgio
authors: G
authors: Inghirami