De novo <i>TP53</i> germline activating mutations in two patients with the phenotype mimicking Diamond–Blackfan anemia

Федорова, Д. В.; Ovsyannikova, Galina; Курникова, М. А.; Pavlova, Anna; Konyukhova, Tatiana; Pshonkin, A. V.; Smetanina, N.S.

doi:10.1002/pbc.29558

Cited by 9 publications

(8 citation statements)

References 20 publications

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“…A deficiency in the transcription factor MYSM1 in mice or humans impairs RP expression and causes TP53-dependent bone marrow failure ( 58 , 59 ). Most importantly, germline activating TP53 mutations cause a clinical phenotype of DBA ( 60 , 61 ). The current work supports these previous studies and provides new experimental approaches to investigate mechanisms of TP53 activation resulting from RP deficiency and the resultant functional outcomes.…”

Section: Discussionmentioning

confidence: 99%

An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity

Bhoopalan¹,

Yen²,

Mayuranathan³

et al. 2023

JCI Insight

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Diamond-Blackfan anemia (DBA) is a genetic blood disease caused by heterozygous loss-offunction mutations in ribosomal protein (RP) genes, most commonly RPS19. The signature feature of DBA is hypoplastic anemia occurring in infants, although some older patients develop multi-lineage cytopenias with bone marrow hypocellularity. The mechanism of anemia in DBA is not fully understood and even less is known about the pancytopenia that occurs later in life, in part because patient hematopoietic stem and progenitor cells (HSPCs) are difficult to obtain, and the current experimental models are suboptimal. We modeled DBA by editing healthy human donor CD34 + HSPCs with CRISPR/Cas9 to create RPS19 haploinsufficiency. In vitro differentiation revealed normal myelopoiesis and impaired erythropoiesis, as observed in DBA.After transplantation into immunodeficient mice, bone marrow repopulation by RPS19 +/− HSPCs was profoundly reduced, indicating hematopoietic stem cell (HSC) impairment. The erythroid and HSC defects resulting from RPS19 haploinsufficiency were partially corrected by transduction with an RPS19-expressing lentiviral vector or by Cas9 disruption of TP53. Our results define a tractable, biologically relevant experimental model of DBA based on genome-editing of primary human HSPCs and they identify an associated HSC defect that emulates the pan-hematopoietic defect of DBA.

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Section: Discussionmentioning

confidence: 99%

An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity

Bhoopalan¹,

Yen²,

Mayuranathan³

et al. 2023

JCI Insight

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“…Thus, defects in telomere maintenance or in the FA DNA repair pathway were long known to cause p53 activation, but our results indicated that, conversely, increased p53 activity might affect telomere function and DNA repair, hence defining positive feedback loops that might contribute to the clinical overlap between DC and FA [26]. Interestingly, the clinical traits of humans with a germline activating TP53 mutation also revealed features of DBA [38][39][40], a bone marrow failure syndrome also partially similar to DC or FA, and mutations in DBA-causal genes are also known to cause p53 activation [9,[66][67][68][69][70]. In that case, however, evidence for a positive feedback loop was not established, because no DBA-causal gene had been reported to be downregulated by p53.…”

Section: Food For Thought: Modeling P53 In a Circuitry Of Genes Assoc...mentioning

confidence: 65%

“…These phenotypes were suggestive of a DBA-like syndrome with additional features more common in DC [38]. Additional patients with similar TP53 mutations were later confirmed to present DBA-like features, but could exhibit normal telomere length [39,40].…”

Section: The Plot Thickens: Germline P53 Activation Underlies Feature...mentioning

confidence: 76%

p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes

Rakotopare,

Toledo

2023

IJMS

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Mice with a constitutive increase in p53 activity exhibited features of dyskeratosis congenita (DC), a bone marrow failure syndrome (BMFS) caused by defective telomere maintenance. Further studies confirmed, in humans and mice, that germline mutations affecting TP53 or its regulator MDM4 may cause short telomeres and alter hematopoiesis, but also revealed features of Diamond–Blackfan anemia (DBA) or Fanconi anemia (FA), two BMFSs, respectively, caused by defects in ribosomal function or DNA repair. p53 downregulates several genes mutated in DC, either by binding to promoter sequences (DKC1) or indirectly via the DREAM repressor complex (RTEL1, DCLRE1B), and the p53-DREAM pathway represses 22 additional telomere-related genes. Interestingly, mutations in any DC-causal gene will cause telomere dysfunction and subsequent p53 activation to further promote the repression of p53-DREAM targets. Similarly, ribosomal dysfunction and DNA lesions cause p53 activation, and p53-DREAM targets include the DBA-causal gene TSR2, at least 9 FA-causal genes, and 38 other genes affecting ribosomes or the FA pathway. Furthermore, patients with BMFSs may exhibit brain abnormalities, and p53-DREAM represses 16 genes mutated in microcephaly or cerebellar hypoplasia. In sum, positive feedback loops and the repertoire of p53-DREAM targets likely contribute to partial phenotypic overlaps between BMFSs of distinct molecular origins.

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“…They also demonstrated that high cell cycle speed was required during MEPs fate decision, and erythroid progenitors have significantly more proliferation than megakaryocyte-committed progenitors by scRNA-seq analysis [ 54 ]. In addition, individuals with gain-of-function mutations in exon 10 of p53 gene were reported to have DBA-like syndromes between DBA and dyskeratosis congenita [ 55 ]. GATA1 was also demonstrated to have impact on p53 inhibition [ 56 ].…”

Section: Introductionmentioning

confidence: 99%

Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia

Liu,

Karlsson

2023

Leukemia

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AbstactDiamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure disorder characterized by erythroid hypoplasia. It primarily affects infants and is often caused by heterozygous allelic variations in ribosomal protein (RP) genes. Recent studies also indicated that non-RP genes like GATA1, TSR2, are associated with DBA. P53 activation, translational dysfunction, inflammation, imbalanced globin/heme synthesis, and autophagy dysregulation were shown to contribute to disrupted erythropoiesis and impaired red blood cell production. The main therapeutic option for DBA patients is corticosteroids. However, half of these patients become non-responsive to corticosteroid therapy over prolonged treatment and have to be given blood transfusions. Hematopoietic stem cell transplantation is currently the sole curative option, however, the treatment is limited by the availability of suitable donors and the potential for serious immunological complications. Recent advances in gene therapy using lentiviral vectors have shown promise in treating RPS19-deficient DBA by promoting normal hematopoiesis. With deepening insights into the molecular framework of DBA, emerging therapies like gene therapy hold promise for providing curative solutions and advancing comprehension of the underlying disease mechanisms.

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De novo TP53 germline activating mutations in two patients with the phenotype mimicking Diamond–Blackfan anemia

Cited by 9 publications

References 20 publications

An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity

An RPS19-edited model for Diamond-Blackfan anemia reveals TP53-dependent impairment of hematopoietic stem cell activity

p53 in the Molecular Circuitry of Bone Marrow Failure Syndromes

Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia

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