Genetic variation and inflammation intersections: GATA2- and RUNX1-linked mechanisms of blood pathogenesis

Germline genetic variation can predispose hematopoietic stem and progenitor cells to bone marrow failure and hematologic malignancies. Why predisposition-causing (conditionally pathogenic, CP) genetic variation is insufficient for pathogenesis is incompletely understood. The current paradigm assumes that CP variation enables secondary genetic mutations and/or epigenetic alterations to instigate pathogenesis. Hematopoietic stem/progenitor cells harboring CP variation can exhibit dysregulated expression of genes encoding inflammatory signaling components. Given the positive and negative autoregulatory loops intrinsic to inflammatory signaling networks, exposing such cells to inflammation would further corrupt the networks and genome function, predisposing cells to malignant transformation. There are many unanswered questions on how signaling machinery alterations impact signaling networks governing genome function in the basal state and in a microenvironment with qualitatively and/or quantitatively aberrant inflammation. Corrupted signaling networks caused by the deleterious combination of inflammation and CP variation intersect with and disrupt physiological mechanisms governing hematopoietic stem and progenitor cell genome function. This review considers how inflammation triggers or amplifies the functional ramifications of CP variation as a blood pathogenic mechanism, with a particular emphasis on GATA2 and RUNX1 transcription factor-linked mechanisms.