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: 13.22). 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.

Download full-text

Full-text

Available from: Meghan Bliss-Moreau, Aug 25, 2014
  • Source
    • "Analysis of gene expression in leukaemic cells from patients with and without DS and functional studies in a mouse model of DS-AMKL identified DYRK1A as a potent megakaryoblastic-tumour promoting gene. Increased DYRK1A dosage and leukaemogenesis in trisomic megakaryocytes was linked to an inhibition of NFAT (Malinge et al., 2012). Recent study identifying DYRK1A as a part of the machinery sustaining permanently open chromatin on rapidly inducible genes (Jang et al., 2014), leading to over-expression of cytokines in DS-associated megakaryoblastic leukaemia, further adds to pro-tumorigenic role of DYRK1A. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein kinases are one of the most studied drug targets in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. Dual-specificity Tyrosine phosphorylation-Regulated Kinase 1A (DYRK1A) has been much less studied compared to many other kinases. DYRK1A primary function occurs during early development, where this protein regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells. Although most extensively characterised for its role in brain development, DYRK1A is over-expressed in a variety of diseases including a number of human malignancies, such as haematological and brain cancers. Here we review the accumulating molecular studies that support our understanding how DYRK1A signalling could underlie these pathological functions. The relevance of DYRK1A in a number of diseases is also substantiated with intensive drug discovery efforts to develop potent and selective inhibitors of DYRK1A. Several classes of DYRK1A inhibitors have recently been disclosed and some molecules are promising leads to develop DYRK1A inhibitors as drugs for DYRK1A-dependent diseases. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Pharmacology [?] Therapeutics
  • Source
    • "Human DYRK1A maps to chromosome 21, and it is overexpressed in Down syndrome (DS) individuals and DS mouse models. This alteration has been correlated with a wide range of the pathological phenotypes associated to DS, such as motor alterations, retinal abnormalities, osteoporotic bone phenotype, craniofacial dysmorphology, or increased risk of childhood leukemia (Arron et al., 2006; Laguna et al., 2008; Lee et al., 2009; Malinge et al., 2012; Ortiz-Abalia et al., 2008). In addition, a few cases of truncating mutations in one DYRK1A allele have been described in patients with general growth retardation and severe primary microcephaly (Courcet et al., 2012; Møller et al., 2008; van Bon et al., 2011), highlighting the extreme dosage sensitivity of this gene. "
    [Show abstract] [Hide abstract]
    ABSTRACT: DYRK1A is a dosage-sensitive protein kinase that fulfills key roles during development and in tissue homeostasis, and its dysregulation results in human pathologies. DYRK1A is present in both the nucleus and cytoplasm of mammalian cells, although its nuclear function remains unclear. Genome-wide analysis of DYRK1A-associated loci reveals that the kinase is recruited preferentially to promoters of genes actively transcribed by RNA polymerase II (RNAPII), which are functionally associated with translation, RNA processing, and cell cycle. DYRK1A-bound promoter sequences are highly enriched in a conserved palindromic motif, which is necessary to drive DYRK1A-dependent transcriptional activation. DYRK1A phosphorylates the C-terminal domain (CTD) of RNAPII at Ser2 and Ser5. Depletion of DYRK1A results in reduced association of RNAPII at the target promoters as well as hypophosphorylation of the RNAPII CTD along the target gene bodies. These results are consistent with DYRK1A being a transcriptional regulator by acting as a CTD kinase. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Molecular cell
  • Source
    • "One such gene is DYRK1A, which encodes the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A. This gene was recently identified as a driver of megakaryocytic leukemia in a mouse DS AMKL model [35]. Neural Cell Adhesion Molecule (NCAM), which was found to be repressed by GATA1, is associated with poorer prognosis in AML [36] and early death in pediatric AML patients [37]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It has been previously shown that acute myeloid leukemia (AML) patients with higher levels of GATA1 expression have poorer outcomes. Furthermore, pediatric Down syndrome (DS) patients with acute megakaryocytic leukemia (AMKL), whose blast cells almost universally harbor somatic mutations in exon 2 of the transcription factor gene GATA1, demonstrate increased overall survival relative to non-DS pediatric patients, suggesting a potential role for GATA1 in chemotherapy response. In this study, we confirmed that amongst non-DS patients, GATA1 transcripts were significantly higher in AMKL blasts compared to blasts from other AML subgroups. Further, GATA1 transcript levels significantly correlated with transcript levels for the anti-apoptotic protein Bcl-xL in our patient cohort. ShRNA knockdown of GATA1 in the megakaryocytic cell line Meg-01 resulted in significantly increased cytarabine (ara-C) and daunorubicin anti-proliferative sensitivities and decreased Bcl-xL transcript and protein levels. Chromatin immunoprecipitation (ChIP) and reporter gene assays demonstrated that the Bcl-x gene (which transcribes the Bcl-xL transcripts) is a bona fide GATA1 target gene in AMKL cells. Treatment of the Meg-01 cells with the histone deacetylase inhibitor valproic acid resulted in down-regulation of both GATA1 and Bcl-xL and significantly enhanced ara-C sensitivity. Furthermore, additional GATA1 target genes were identified by oligonucleotide microarray and ChIP-on-Chip analyses. Our findings demonstrate a role for GATA1 in chemotherapy resistance in non-DS AMKL cells, and identified additional GATA1 target genes for future studies.
    Full-text · Article · Jul 2013 · PLoS ONE
Show more