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 Article has an altmetric score of 14

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 6

Dyrk1a is a prominent megakaryocytic tumor-promoting gene.

Options: View larger image (or click on image) Download as PowerPoint
Dyrk1a is a prominent megakaryocytic tumor-promoting gene. (A) Fold...
(A) Fold change gene expression values of Dyrk1a, Chaf1b, and Hlcs, as assessed by real-time PCR, in CD41-positive cells isolated from spleens of Gata1s/Ts1Rhr/MPL W515L recipient mice, compared with those in Gata1s/MPL W515L CD41-selected spleen cells 4 weeks posttransplantation. Mean ± SD. (B) Representative flow cytometry plots depicting the proportion of CD41+ cells derived from cultures of bone marrow progenitors infected with Dyrk1a, CHAF1B, or HLCS encoding viruses or control vector. Percentages of live cells are indicated. (C) Overexpression of Dyrk1a leads to reduced polyploidization of megakaryocytes. Mean ± SD (n = 3–5 per group). *P < 0.004, **P < 0.0008 compared with control infected. (D) Fold change increase in percentage of CD41+ and CD42+ cells after expression of wild-type or kinase-inactive alleles of Dyrk1a in wild-type or Gata1s bone marrow progenitors. Mean percentages ± SD (n = 2–4 per group). (E) Representative flow cytometry plots of Dyrk1a shRNA and control infected progenitors cells cultured under megakaryocytic conditions. Bone marrow cells were derived from Ts1Rhr and Gata1s/Ts1Rhr mice. Percentages of live cells are indicated. (F) Treatment of double (Gata1s/MPL W515L) and triple (Gata1s/Ts1Rhr/MPL W515L) mutant cells with harmine reveals that trisomic cells are more sensitive to DYRK1A inhibition in vitro. Mean ± SD (n = 3–4 per group).