GATA2-TGF-b1 axis regulates human NK cell development

Natural killer (NK) cells, a subset of innate lymphocytes, produce proinflammatory cytokines and mediate anti-tumor cytotoxicity. GATA2 is a master transcription factor that is essential for the development of erythroid, myeloid, B, and NK cells. Patients with GATA2 haploinsufficiency lack CD56 brightNK cells (immature), with or without a reduction in the number of CD56 dimNK cells (mature). However, how GATA2 functions to establish and maintain genetic networks during the development and function of human NK cells is unknown. Here, we identify a novel GATA2-TGF-b1 axis that regulates NK cell development. We performed single-cell RNA-seq with NK cells from three GATA2 T354Mpatients and found significantly reduced expression of immediate early genes, which indicated that they are functionally-defective. We discovered a reduction in TGF-b1 transcripts and defective expression of TGF-b1 target genes in NK cells from GATA2 T354Mpatients. Using a reporter assay, we determined that GATA2 occupy to TGFB1 promoter, and this association was decreased in GATA2 T354MNK cells. ATAC-seq of GATA2 T354MNK cells indicates significantly altered chromatin accessibility. GATA2 CUT&Tag-seq validated that it occupies the TGFB1 promoter region, which correlated with activation of the TGFB1 locus in human NK cells. In summary, we define a mechanism by which GATA2 controls TGF-b1 production in human NK cells and thereby regulating their development. These findings provide vital clues for developmental and functional defects of NK cells in GATA2 T354Mpatients. ASH Graduate Hematology Award (D.W.); GIRT Award from MCW-C4I (D.W.); NIH R01 AI102893 and NCI R01 CA179363 (S.M.); HRHM Program of MACC Fund (S.M.), Nicholas Family Foundation (S.M.); Gardetto Family (S.M.); MCW-Cancer Center-Large Seed Grant (S.M. and M.S.T.); MACC Fund (S.M.); Ann’s Hope Mela- noma Foundation (S.M.); and Advancing Healthier Wisconsin (S.M.)