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.
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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

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Figure 4

ERG, DYRK1A, CHAF1B, and HLCS are leading candidate DS leukemia-promoting oncogenes.

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ERG, DYRK1A, CHAF1B, and HLCS are leading candidate DS leukemia-promoti...
(A) Schematic representation of the strategy used to assess the functional implication of trisomic genes in human DS-AMKL cell lines. (B) RT-PCR of the DSCR and nearby genes selected for the functional screening in various cell lines, including DS-AMKL lines CMK and CMY (left panel). Red type indicates Ts1Rhr mice; green type indicates Ts1Cje mice; blue type indicates Ts65Dn mice; and black type indicates Tc1 mice. D, DMSO treated; T, TPA treated. Knockdown efficiency of the selected genes in the CMY cell lines (right panel). We hypothesize that a knockdown efficiency of at least 33% (0.66 threshold) artificially recapitulates the disomy of euploid cells. (C) Plots of normalized values of CD42 expression and DNA content of shRNA-infected CMY cells after treatment for 3 days with TPA. Changes outside of 2 SDs from the mean (red box) were considered significant. (D) Representative flow cytometry plots, showing effect of the DYRK1A, CHAF1B, and HLCS knock down during TPA-induced megakaryocytic differentiation of CMK cells. Percentages of live cells are indicated. Knockdown efficiency (KD eff) is shown. exp, expression; puro, puromycin selection.