ArticleThe Journal of clinical investigation2012
Increased dosage of the chromosome 21 ortholog Dyrk1a promotes megakaryoblastic leukemia in a murine model of Down syndrome.
Article in The Journal of clinical investigation, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers.
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Who cites it
99 citing papers in PubMed, 178 citations in OpenAlex.
- Small-molecule inhibitors of the protein kinase DYRK as potential therapeutic candidates in cancer.Cell chemical biology · 2026Article
- Perspectives on the origin and therapeutic opportunities in Down syndrome-associated leukemia.Cancer metastasis reviews · 2025Review
- Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL.Signal transduction and targeted therapy · 2025Article
- Epigenetic Regulation of Erythropoiesis: From Developmental Programs to Therapeutic Targets.International journal of molecular sciences · 2025Review
- DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to BCL2 inhibition.Leukemia · 2025Article
- DYRK1A in blood and immune function: implications in leukemia, inflammatory disorders, infection and Down syndrome.Frontiers in cell and developmental biology · 2025Review
- Article
- A rare presentation and treatment challenges for multiple myeloma in down syndrome: A case report and literature review.Clinical case reports · 2024Article
- Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer.International journal of molecular sciences · 2024Review
- The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program.HemaSphere · 2024Article
- Article
- Review
- Aberrant stem cell and developmental programs in pediatric leukemia.Frontiers in cell and developmental biology · 2024Review
- Down syndrome-associated leukaemias: current evidence and challenges.Therapeutic advances in hematology · 2024Review
- Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis.JCI insight · 2023Article
- Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.Journal of natural products · 2023Article
- Down syndrome and leukemia: from basic mechanisms to clinical advances.Haematologica · 2023Review
- DYRK1A-mediated PLK2 phosphorylation regulates the proliferation and invasion of glioblastoma cells.International journal of oncology · 2023Article
- B cell class switch recombination is regulated by DYRK1A through MSH6 phosphorylation.Nature communications · 2023Article
- RUNX1 isoform disequilibrium promotes the development of trisomy 21-associated myeloid leukemia.Blood · 2023Article
39 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
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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