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Conditionally Pathogenic Genetic Variants of a Hematopoietic Disease-Suppressing Enhancer

ABSTRACT: Human genetic variants are classified based on potential pathogenicity to guide clinical decisions. However, mechanistic uncertainties often preclude definitive categorization. Germline coding and enhancer variants within the hematopoietic regulator GATA2 create a bone marrow failure and leukemia predisposition. The conserved murine enhancer promotes hematopoietic stem cell (HSC) genesis, and a single-nucleotide human variant in an Ets motif attenuates chemotherapy-induced hematopoietic regeneration. We describe “conditionally pathogenic” (CP) enhancer motif variants that differentially impact hematopoietic development and regeneration. The Ets motif variant functioned cell-autonomously in hematopoietic cells to disrupt hematopoiesis. Since an epigenetically-silenced normal allele can exacerbate phenotypes of a pathogenic heterozygous variant, we engineered a bone marrow failure model harboring the Ets motif variant and a severe enhancer mutation on the second allele. Despite normal developmental hematopoiesis, regeneration in response to chemotherapy, inflammation, and a therapeutic HSC mobilizer was compromised. The CP paradigm informs mechanisms underlying phenotypic plasticity and clinical genetics.

ORGANISM(S): Mus musculus

PROVIDER: GSE179790 | GEO | 2021/12/15

REPOSITORIES: GEO

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