Article

Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.

Division of Hematology/Oncology, Northwestern University, Chicago, Illinois 60611, USA.
The Journal of clinical investigation (impact factor: 15.39). 03/2012; 122(3):948-62. DOI:10.1172/JCI60455
Source: PubMed

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.

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Keywords

33 orthologs
 
Acquired mutations
 
activated T cells
 
acute megakaryoblastic leukemia
 
calcineurin/NFAT pathway inhibition
 
chromosome 21 genes
 
clonal preleukemia
 
decreased risk
 
decreased tumor incidence
 
GATA1 mutations
 
germline GATA1 mutations analogous
 
leukemogenesis
 
markedly increased risk
 
megakaryoblastic leukemia
 
nuclear factor
 
potent megakaryoblastic tumor-promoting gene
 
promote megakaryoblastic leukemia
 
transcription factor-encoding GATA1 gene
 
transient myeloproliferative disorder
 
trisomic genes
 

Sébastien Malinge