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This study identifies germline MDM4 loss-of-function mutations as a novel cause of bone marrow failure (BMF) syndromes characterized by heightened p53 activation. Mutations impair MDM4’s regulatory control over p53, leading to defective hematopoiesis including hypocellular myelodysplastic syndrome (MDS). CRISPR-edited hematopoietic stem cells demonstrate functional deficits, corroborated in patient-derived induced pluripotent stem cells (iPSCs), underscoring MDM4’s critical role in maintaining bone marrow homeostasis. Notably, somatic TP53 mutations arise in disease progression, indicating complex rescue mechanisms.
