Genetic bone marrow failure conditions are caused by mutations affecting a variety of cellular pathways including DNA repair, telomere maintenance, ribosome assembly, and transcriptional regulation. Many of these genetic bone marrow failure conditions carry an increased risk of myeloid malignancy, which is a major cause of mortality for these patients. Clonal hematopoiesis frequently develops in patients with bone marrow failure. Recent studies have elucidated maladaptive clonal pathways that drive towards malignancy, as well as adaptive clonal pathways that result in somatic rescue from the germline genetic stressor. These somatic patterns of clonal hematopoiesis are informing rational strategies for surveillance to guide timely interventions preventing progression to malignancy. The effects of somatic mutation cell of origin and cell state of the mutated clones will be discussed.
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