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Although certain human genetic variants are conspicuously loss-of-function, decoding the impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two 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 Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling promotes bone marrow failure, GATA2-deficiency patient phenotypes, these results inform mechanisms underlying GATA2-linked pathologies.

Original publication




Journal article


J Clin Invest

Publication Date



Genetic variation, Genetics, Hematology, Signal transduction, Transcription