Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome
Sébastien Malinge, … , Sandeep Gurbuxani, John D. Crispino
Sébastien Malinge, … , Sandeep Gurbuxani, John D. Crispino
Published February 22, 2012
Citation Information: J Clin Invest. 2012;122(3):948-962. https://doi.org/10.1172/JCI60455.
View: Text | PDF
Research Article

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

Sébastien Malinge, Meghan Bliss-Moreau, Gina Kirsammer, Lauren Diebold, Timothy Chlon, Sandeep Gurbuxani, John D. Crispino

×

Figure 3

Three oncogenic events, including a partial trisomy 21, cooperate to promote DS-MkL in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Three oncogenic events, including a partial trisomy 21, cooperate to pro...
(A) Survival curves of mice transplanted with different combinations of oncogenic events (n = 6–13 per group). (B) Platelet counts of recipient mice 4 weeks after transplantation. Mean ± SD (n = 4–12 per group). (C) H&E-stained spleen sections of MPL W515L–overexpressing transplanted mice at 4 weeks after transplant (original magnification, ×400). (D) von Willebrand factor immunostaining of MPL W515L–overexpressing recipient mice 4 weeks after transplant, showing the complete megakaryocytic infiltration of the spleen only in the triple mutant mice (original magnification, ×400). (E) Representative flow cytometry plots reveal that triple mutants display marked megakaryocytic expansion in the spleen, while double or single mutants show neutrophilia. Percentages of live cells are indicated.