GATA2 +9.5 enhancer: from principles of hematopoiesis to genetic diagnosis in precision medicine.

Abstract

By establishing mechanisms that deliver oxygen to sustain cells and tissues, fight life-threatening pathogens and harness the immune system to eradicate cancer cells, hematopoietic stem and progenitor cells (HSPCs) are vital in health and disease. The cell biological framework for HSPC generation has been rigorously developed, yet recent single-cell transcriptomic analyses have unveiled permutations of the hematopoietic hierarchy that differ considerably from the traditional roadmap. Deploying mutants that disrupt specific steps in hematopoiesis constitutes a powerful strategy for deconvoluting the complex cell biology. It is striking that a single transcription factor, GATA2, is so crucial for HSPC generation and function, and therefore it is instructive to consider mechanisms governing GATA2 expression and activity. The present review focuses on an essential GATA2 enhancer (+9.5) and how +9.5 mutants inform basic and clinical/translational science. +9.5 is essential for HSPC generation and function during development and hematopoietic regeneration. Human +9.5 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. Qualitatively and quantitatively distinct contributions of +9.5 cis-regulatory elements confer context-dependent enhancer activity. The discovery of +9.5 and its mutant alleles spawned fundamental insights into hematopoiesis, and given its role to suppress blood disease emergence, clinical centers test for mutations in this sequence to diagnose the cause of enigmatic cytopenias. Multidisciplinary approaches to discover and understand cis-regulatory elements governing expression of key regulators of hematopoiesis unveil biological and mechanistic insights that provide the logic for innovating clinical applications.