1008 – FROM GATA2 HUMAN GENETICS TO LEUKEMIA PREDISPOSITION-GENERATING NETWORKS

While certain genetic variants are conspicuously loss-of-function, decoding the impact of many variants can be challenging. 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). We used genomic technologies in Gata2 enhancer-mutant hematopoietic progenitors to reveal how the insertion impacts GATA2 function genome-wide. Despite being nuclear-localized, 9aa-Ins was severely defective, with activation more impaired than repression. Variation of the zinc finger spacer length revealed that repression tolerated insertions that were detrimental to activation. GATA2 deficiency generated hematopoiesis-disrupting networks involving cytokine and pattern recognition receptors, which are predicted to cause hallmark phenotypes of GATA2 deficiency syndrome. As these alterations render progenitors hypersensitive to inflammatory stimuli, the combined predisposition mutation and hypersensitivity phenotype may be particularly deleterious to HSPCs. Analyses with additional GATA2 disease-linked variants confirmed and extended these conclusions. These results establish principles underlying GATA factor function, and comparable systems are being deployed to elucidate additional predisposition mechanisms.