Conditionally pathogenic genetic variants of a hematopoietic disease–suppressing enhancer
Alexandra A. Soukup, Daniel R. Matson, Peng Liu, Kirby D. Johnson, Emery H. Bresnick
Abstract
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 affect hematopoietic development and regeneration. The Ets motif variant functioned autonomously in hematopoietic cells to disrupt hematopoiesis. Because 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.