Pathogenic GATA2 genetic variants utilize an obligate enhancer mechanism to distort a multilineage differentiation program

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 10; p. e2317147121
• Main Authors: Katsumura, Koichi R, Liu, Peng, Kim, Jeong-Ah, Mehta, Charu, Bresnick, Emery H
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05-03-2024
• Subjects: Biological Sciences; Bone marrow; CCAAT/enhancer-binding protein; Cell differentiation; Cell Differentiation - genetics; Differentiation; GATA2 Transcription Factor - genetics; Gene regulation; Genetic diversity; Genetic variance; Genotype; Hematopoietic Stem Cells; Hemopoiesis; Humans; Leukemia; Leukocytes (eosinophilic); Lymphocytes; Lymphocytes T; Monocytes; Pathogenesis; Progenitor cells; Regulatory Sequences, Nucleic Acid; Transcription factors; Zinc finger proteins; hematopoiesis; differentiation; transcription; GATA2; GATA
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2317147121

Mutations in genes encoding transcription factors inactivate or generate ectopic activities to instigate pathogenesis. By disrupting hematopoietic stem/progenitor cells, GATA2 germline variants create a bone marrow failure and leukemia predisposition, GATA2 deficiency syndrome, yet mechanisms underlying the complex phenotypic constellation are unresolved. We used a GATA2-deficient progenitor rescue system to analyze how genetic variation influences GATA2 functions. Pathogenic variants impaired, without abrogating, GATA2-dependent transcriptional regulation. Variants promoted eosinophil and repressed monocytic differentiation without regulating mast cell and erythroid differentiation. While GATA2 and T354M required the DNA-binding C-terminal zinc finger, T354M disproportionately required the N-terminal finger and N terminus. GATA2 and T354M activated a CCAAT/Enhancer Binding Protein-ε (C/EBPε) enhancer, creating a feedforward loop operating with the T-cell Acute Lymphocyte Leukemia-1 (TAL1) transcription factor. Elevating C/EBPε partially normalized hematopoietic defects of GATA2-deficient progenitors. Thus, pathogenic germline variation discriminatively spares or compromises transcription factor attributes, and retaining an obligate enhancer mechanism distorts a multilineage differentiation program.