title: Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.
abstract: Individuals with Down syndrome (DS; also known as trisomy 21) have a markedly increased risk of leukemia in childhood but a decreased risk of solid tumors in adulthood. Acquired mutations in the transcription factor-encoding GATA1 gene are observed in nearly all individuals with DS who are born with transient myeloproliferative disorder (TMD), a clonal preleukemia, and/or who develop acute megakaryoblastic leukemia (AMKL). Individuals who do not have DS but bear germline GATA1 mutations analogous to those detected in individuals with TMD and DS-AMKL are not predisposed to leukemia. To better understand the functional contribution of trisomy 21 to leukemogenesis, we used mouse and human cell models of DS to reproduce the multistep pathogenesis of DS-AMKL and to identify chromosome 21 genes that promote megakaryoblastic leukemia in children with DS. Our results revealed that trisomy for only 33 orthologs of human chromosome 21 (Hsa21) genes was sufficient to cooperate with GATA1 mutations to initiate megakaryoblastic leukemia in vivo. Furthermore, through a functional screening of the trisomic genes, we demonstrated that DYRK1A, which encodes dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A, was a potent megakaryoblastic tumor-promoting gene that contributed to leukemogenesis through dysregulation of nuclear factor of activated T cells (NFAT) activation. Given that calcineurin/NFAT pathway inhibition has been implicated in the decreased tumor incidence in adults with DS, our results show that the same pathway can be both proleukemic in children and antitumorigenic in adults.
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Malinge
authors.forename: Meghan
authors.initials: M
authors.lastname: Bliss-Moreau
authors.forename: Gina
authors.initials: G
authors.lastname: Kirsammer
authors.forename: Lauren
authors.initials: L
authors.lastname: Diebold
authors.forename: Timothy
authors.initials: T
authors.lastname: Chlon
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D019703:Calcineurin / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000150:complications / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D012306:Risk; D013922:Thrombocytosis / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D019703:Calcineurin; D050982:GATA1 Transcription Factor; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse