ArticleThe Journal of clinical investigation2023
Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 16 citations in OpenAlex.
- MLL3 and MLL4 sustain hematopoietic stem cell multipotency by opposing a B-cell default state.Blood · 2026Article
- GATA2 decommissioning of enhancers: A mechanism to constrain inflammatory signaling.Cell reports · 2025Article
- Dual mechanism of inflammation sensing by the hematopoietic progenitor genome.Science advances · 2025Article
- Article
- Loss of GATA2 promotes invasion and predicts cancer recurrence and survival in uterine serous carcinoma.JCI insight · 2025Article
- BmNPV interacts with super-enhancer regions of the host chromatin to hijack cellular transcription machinery.Nucleic acids research · 2025Article
- Pathogenic GATA2 genetic variants utilize an obligate enhancer mechanism to distort a multilineage differentiation program.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Linking GATA2 to myeloid dysplasia and complex cytogenetics in adult myelodysplastic neoplasm and acute myeloid leukemia.Blood advances · 2024Article
- A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice.The Journal of clinical investigation · 2023Article
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Authors and funding
20 authors at 7 institutions in 4 countries.
Funding
Abstract
Although certain human genetic variants are conspicuously loss of function, decoding the impact of many variants is challenging. Previously, we described a patient with leukemia predisposition syndrome (GATA2 deficiency) with a germline GATA2 variant that inserts 9 amino acids between the 2 zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies and a genetic rescue system with Gata2 enhancer-mutant hematopoietic progenitor cells to compare how GATA2 and 9aa-Ins function genome-wide. Despite nuclear localization, 9aa-Ins was severely defective in occupying and remodeling chromatin and regulating transcription. Variation of the inter-zinc finger spacer length revealed that insertions were more deleterious to activation than repression. GATA2 deficiency generated a lineage-diverting gene expression program and a hematopoiesis-disrupting signaling network in progenitors with reduced granulocyte-macrophage colony-stimulating factor (GM-CSF) and elevated IL-6 signaling. As insufficient GM-CSF signaling caused pulmonary alveolar proteinosis and excessive IL-6 signaling promoted bone marrow failure and GATA2 deficiency patient phenotypes, these results provide insight into mechanisms underlying GATA2-linked pathologies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.