MDM4 HAPLOINSUFFICIENCY LEADS TO P53-MEDIATED BONE MARROW FAILURE - PubMed
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- #MDM4
- #p53
- #bone marrow failure
- Six unrelated individuals with bone marrow failure (BMF) and hypocellular myelodysplastic syndrome (MDS) were studied, with a median age of onset at 10 years.
- Germline heterozygous variants in MDM4 were identified, including four null and two missense variants, leading to loss-of-function and enhanced p53 activation.
- CRISPR/Cas9 deletion of MDM4 in hematopoietic stem and progenitor cells (HSPCs) resulted in increased p53 activity, impaired colony-forming capacity, and reduced engraftment potential.
- Patient-specific MDM4 variants introduced into induced pluripotent stem cells (iPSCs) showed reduced erythroid and myeloid cell production and increased p53 activity.
- Transcriptome analysis of iPSC-derived hematopoietic cells revealed upregulation of the p53 pathway, confirming MDM4's role in regulating hematopoiesis through p53.
- One patient with MDS acquired loss-of-function TP53 mutations, suggesting maladaptive somatic rescue.
- MDM4 deficiency is established as a TP53 activating syndrome associated with BMF and variable hematopoietic manifestations.