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MDM4 overexpression alleviates developmental and hematopoietic defects in Fancg deficient mice.

ABSTRACT: Fanconi anemia (FA) is the most frequent inherited cause of bone marrow failure (BMF). Most FA patients experience hematopoietic stem cell attrition and cytopenia during childhood, which along with intrinsic chromosomal instability, favor clonal evolution and the frequent emergence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in their teens or young adulthood. In the present study, we have developed a joint molecular and cellular approach to get further insights into the mechanisms that set this "pre-leukemic" state up. For this purpose, we developed a mouse model of MDM4 overexpression by introducing a wide genomic region surrounding the gene that includes its proximal regulatory sequences. Finally, we evaluated the consequences of alteration of the FA pathway in HSPCs in KO or in KOTg mice at steady state and under Poly-IC (pIC) stress.

ORGANISM(S): Mus musculus

PROVIDER: GSE288125 | GEO | 2026/06/24

REPOSITORIES: GEO

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MDM4-related bone marrow failure

Project description:We report 6 unrelated individuals with variable BMF phenotypes and hypocellular MDS. The median age at presentation was 10 years (4 weeks - 53 years). Unbiased genomic analysis revealed germline heterozygous variants in MDM4, including 4 null (frameshift, nonsense, and splice-site resulting in premature truncation confirmed by RNA sequencing) and 2 missense variants. Mechanistically, MDM4 mutations lead to loss-of-function with enhanced p53 activation. We used CRISPR/Cas9 to delete MDM4 in healthy donor hematopoietic stem and progenitor cells (HSPCs). The resulting MDM4-haploinsufficient HSPCs exhibited increased p53 activity, impaired colony-forming capacity, and reduced engraftment potential in immunodeficient mice. Complementation studies revealed the functional necessity of both p53-binding and RING-finger domains in MDM4-mediated hematopoietic regulation. To study variant effect in a genetic background free of potential confounders, we introduced patient-specific MDM4 variants into induced pluripotent stem cells (iPSCs). MDM4-mutant iPSCs yielded significantly reduced erythroid and myeloid cell populations and exhibited increased p53 activity, as evidenced by elevated p21 expression, confirming the role of MDM4 in regulating hematopoiesis through p53 modulation. Transcriptome analysis of iPSC-derived hematopoietic cells revealed upregulation of p53 pathway. Importantly, one patient acquired TP53 mutations, suggesting clonal rescue in the context of MDM4 deficiency. Our findings establish MDM4 deficiency as a new “TP53-opathy” BMF syndrome with variable hematopoietic manifestations. This study also highlights the critical role of the MDM4-p53 axis in maintaining hematopoietic homeostasis.

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Pluripotent cell models of Fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors

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Project description:Fanconi anemia (FA) is a rare inherited bone marrow failure (BMF) syndrome, caused by mutation in one of at least 23 proteins in the FA complementation group. The mechanism of BMF in FA is currently unknown. Previous studies have shown that functional defects in hematopoeitic stem and progenitor cells (HSPC) arise spontaneously in response to developmental replication stress in murine FA fetal livers (FL) as early as 13.5 dpc. In this study, we harvested E13.5 wild-type (WT) and Fancd2-/- FL from three pregnancies, depleted samples of erythroid progenitors via FACS against Ter-119, and performed single-cell RNA sequencing. Our goal was to identify which popoulations in the fetal liver at this time point show severe transcriptional dysregulation, as well as to identify what cellular processes in these populations are most affected, in order to gain insight into the mechanism of BMF in FA and guide future studies.

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Pluripotent cell models of Fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors

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A Defective Splicing Machinery Promotes Senescence through MDM4 Alternative Splicing

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