The prognostic value of p53 mutation in pediatric marrow hypoplasia

Abo-Elwafa, Hasnaa A.; Attia, Fadia M.; Sharaf, Alzahraa E A

doi:10.1186/1746-1596-6-58

Cited by 4 publications

(3 citation statements)

References 22 publications

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“…Our findings have clinical implications. The observation that TP53 disruption restores bone marrow repopulation capacity to RPS19 +/– HSCs raises the possibility that selective pressure could expand DBA patient HSPCs with somatic loss-of-function TP53 mutations, analogous to what occurs in other bone marrow failure disorders, including Shwachman-Bodian-Diamond syndrome ( 72 ), Fanconi anemia ( 73 ), and dyskeratosis congenita ( 74 ). An increased rate of clonal hematopoiesis with TP53 mutations has not been reported for DBA, although rates of myelodysplastic syndrome and myeloid leukemia are mildly elevated ( 75 ).…”

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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“…In addition, ESCC in FA patients is often associated with infection by human papillomaviruses, which contain E6 protein to suppress p53 activity [ 54 , 55 , 56 ]. Furthermore, p53 dysfunction promotes leukemogenesis in FA patients [ 57 , 58 ]. Therefore, further investigation is warranted to investigate how p53 and FA proteins collectively affect acetaldehyde‐induced DNA damage and repair processes in esophageal carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

FANCD2 limits acetaldehyde‐induced genomic instability during DNA replication in esophageal keratinocytes

et al. 2021

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“…The tumor suppressor gene p53 is involved in the control of cell proliferation, particularly in stressed cells. p 53 gene mutations are the most frequent genetic event found in various types of cancers [33,34], and is the most common studied tumor suppressor gene in ovarian carcinomas. High-grade serous tumors tended to be p53 positive and p53 positivity is related to the survival rate.…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemistry with apoptotic-antiapoptotic proteins (p53, p21, bax, bcl-2), c-kit, telomerase, and metallothionein as a diagnostic aid in benign, borderline, and malignant serous and mucinous ovarian tumors

et al. 2012

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BackgroundIn many tumors including ovarian cancer, cell proliferation and apoptosis are important in pathogenesis and there are many alterations in most of the genes related to the cell cycle. This study was designed to evaluate immunohistochemistry with apoptotic-antiapoptotic proteins (p53, p21, bax, and bcl-2), c-kit, telomerase, and metallothionein as a diagnostic aid in typing of benign, borderline, and malignant serous and mucinous ovarian tumors.MethodsTotal of 68 ovarian tumors, 25 benign [13 (19.1%) serous and12 (17.6%) mucinous], 16 borderline [9 (13.2%) serous and 7(10.3%) mucinous], and 27 malignant ovarian tumors [24 (35.3%) serous and 3 (4.4%) mucinous tumors] were included in the study. Immunohistochemical expression of p53, p21, bax, bcl–2, telomerase, c-kit, and metallothionein were evaluated.ResultsWhen all 68 cases were evaluated as benign, borderline, and malignant ovarian tumors without considering histopathological subtypes, the p53, p21, bax and metallothionein showed significantly higher staining scores in the borderline and malignant ones (p < 0.05). After evaluation of all 68 cases, the serous tumors showed significantly higher staining scores of p53, p21, c-kit, and metallothionein compared to the mucinous ones (p < 0.05). For differentiation of benign and borderline and malignant tumors combined, p53 was not used because all benign tumors has no staining, and p21, bax, and metallothionein was determined the significant predictors for borderline and malignant tumors combined (p < 0.05). For differentiation of borderline and malignant tumors, only p53 was determined the significant predictor for malignant tumors (p < 0.05).ConclusionsIn conclusion, p53, p21, bax, c-kit, and metallothionein may be helpful for the typing of ovarian tumors as benign, borderline and malignant or serous and mucinous. p53, p21, bax, c-kit, and metallothionein may have different roles in the pathogenesis of ovarian tumor types. p53 and metallothionein may be helpful in the typing of borderline and malignant ovarian tumors. The immunohistochemical staining with bcl-2 and telomerase may not provide meaningful contribution for the typing of ovarian tumors.Virtual slideThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2013030833768498

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The prognostic value of p53 mutation in pediatric marrow hypoplasia

Cited by 4 publications

References 22 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

FANCD2 limits acetaldehyde‐induced genomic instability during DNA replication in esophageal keratinocytes

Immunohistochemistry with apoptotic-antiapoptotic proteins (p53, p21, bax, bcl-2), c-kit, telomerase, and metallothionein as a diagnostic aid in benign, borderline, and malignant serous and mucinous ovarian tumors

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