ArticleThe Journal of clinical investigation2022
Stepwise GATA1 and SMC3 mutations alter megakaryocyte differentiation in a Down syndrome leukemia model.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- A novelHaematologica · 2026Article
- Single cell transcriptional evolution of myeloid leukemia of Down syndrome.Nature communications · 2026Article
- Functional classification of platelet gene variants using CRISPR HDR in CD34American journal of human genetics · 2025Article
- Perspectives on the origin and therapeutic opportunities in Down syndrome-associated leukemia.Cancer metastasis reviews · 2025Review
- Single-cell transcriptomics reveal individual and cooperative effects of trisomy 21 and GATA1s on hematopoiesis.Stem cell reports · 2025Article
- Understanding Human Oncogene Function and Cooperativity in Myeloid Malignancy Using iPSCs.Experimental hematology · 2025Review
- The effect of decitabine on human induced pluripotent stem cells (hiPSCs) derived CD34American journal of stem cells · 2025Article
- Article
- ZNF521 promotes acute myeloid leukemogenesis by suppressing the expression and acetylation of SMC3.Heliyon · 2024Article
- Developmental interplay between transcriptional alterations and a targetable cytokine signaling dependency in pediatric ETO2::GLIS2 leukemia.Molecular cancer · 2024Article
- Clinical and Molecular Characteristics of Megakaryocytes in Myelodysplastic Syndrome.Global medical genetics · 2024Article
- Article
- GATA1 in Normal and Pathologic Megakaryopoiesis and Platelet Development.Advances in experimental medicine and biology · 2024Review
- Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis.JCI insight · 2023Article
- Down syndrome and leukemia: from basic mechanisms to clinical advances.Haematologica · 2023Review
- RUNX1 isoform disequilibrium promotes the development of trisomy 21-associated myeloid leukemia.Blood · 2023Article
- Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy.Frontiers in oncology · 2023Review
- Dissecting stepwise mutational impairment of megakaryopoiesis in a model of Down syndrome-associated leukemia.The Journal of clinical investigation · 2022Article
- Advances in molecular characterization of myeloid proliferations associated with Down syndrome.Frontiers in genetics · 2022Review
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Authors and funding
27 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modeled the megakaryocyte differentiation defect through stepwise gene editing of GATA1s, SMC3+/-, and MPLW515K, providing 20 different T21 or disomy 21 (D21) induced pluripotent stem cell (iPSC) clones. GATA1s profoundly reshaped iPSC-derived hematopoietic architecture with gradual myeloid-to-megakaryocyte shift and megakaryocyte differentiation alteration upon addition of SMC3 and MPL mutations. Transcriptional, chromatin accessibility, and GATA1-binding data showed alteration of essential megakaryocyte differentiation genes, including NFE2 downregulation that was associated with loss of GATA1s binding and functionally involved in megakaryocyte differentiation blockage. T21 enhanced the proliferative phenotype, reproducing the cellular and molecular abnormalities of DS-AMKL. Our study provides an array of human cell-based models revealing individual contributions of different mutations to DS-AMKL differentiation blockage, a major determinant of leukemic progression.
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