Heightened DNA damage response impairs hematopoiesis in Fanconi anemia

Dokal, Inderjeet

doi:10.3324/haematol.2012.073643

Cited by 5 publications

(2 citation statements)

References 3 publications

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“…It has been reported that Fanconi anemia pathway is critical for the repair of DNA cross-link damage [ 26 ]. Biallelic mutations in any of 15 FANC genes will result in Fanconi anemia (FA), which can most frequently develop into inherited bone marrow failure (BMF) syndrome [ 72 ]. The work of Raphael Ceccaldi et al revealed that the FA patients showed profound HSPCs defect before the onset of BMF [ 73 ].…”

Section: Discussionmentioning

confidence: 99%

TopBP1 Governs Hematopoietic Stem/Progenitor Cells Survival in Zebrafish Definitive Hematopoiesis

Gao

et al. 2015

PLoS Genet

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In vertebrate definitive hematopoiesis, nascent hematopoietic stem/progenitor cells (HSPCs) migrate to and reside in proliferative hematopoietic microenvironment for transitory expansion. In this process, well-established DNA damage response pathways are vital to resolve the replication stress, which is deleterious for genome stability and cell survival. However, the detailed mechanism on the response and repair of the replication stress-induced DNA damage during hematopoietic progenitor expansion remains elusive. Here we report that a novel zebrafish mutantcas003 with nonsense mutation in topbp1 gene encoding topoisomerase II β binding protein 1 (TopBP1) exhibits severe definitive hematopoiesis failure. Homozygous topbp1cas003 mutants manifest reduced number of HSPCs during definitive hematopoietic cell expansion, without affecting the formation and migration of HSPCs. Moreover, HSPCs in the caudal hematopoietic tissue (an equivalent of the fetal liver in mammals) in topbp1cas003 mutant embryos are more sensitive to hydroxyurea (HU) treatment. Mechanistically, subcellular mislocalization of TopBP1cas003 protein results in ATR/Chk1 activation failure and DNA damage accumulation in HSPCs, and eventually induces the p53-dependent apoptosis of HSPCs. Collectively, this study demonstrates a novel and vital role of TopBP1 in the maintenance of HSPCs genome integrity and survival during hematopoietic progenitor expansion.

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Section: Discussionmentioning

confidence: 99%

TopBP1 Governs Hematopoietic Stem/Progenitor Cells Survival in Zebrafish Definitive Hematopoiesis

Gao

et al. 2015

PLoS Genet

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“…Hematopoiesis in FA is impaired from the earliest stages of embryonic development [ 34 ], and there is a body of evidence supporting the role of dysfunctional HSC biology in the etiology of the disease [ 35 ]. Progression to BMF has been considered to be caused by two different mechanisms: the accumulation of OS-induced DNA damage along mitotic divisions, by deficiency in the FA/BRCA repair pathway, resulting in p53 activation and apoptosis of the hematopoietic progenitors [ 36 , 37 ] and overproduction of inhibitory cytokines, which can degrade bone marrow [ 38 ], leading to impaired erythropoiesis and RBC degradation. In a recent work a novel connection was established between stress hematopoiesis and the occurrence of DNA damage and functional decline in HSCs: it was shown that DNA damage can be a consequence of the exit of HSCs from their homeostatic quiescent state in response to physiological stress, such as infection [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Increased red cell distribution width in Fanconi anemia: a novel marker of stress erythropoiesis

Sousa

Gonçalves²,

Guerra

et al. 2016

Orphanet J Rare Dis

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BackgroundRed cell distribution width (RDW), a classical parameter used in the differential diagnosis of anemia, has recently been recognized as a marker of chronic inflammation and high levels of oxidative stress (OS). Fanconi anemia (FA) is a genetic disorder associated to redox imbalance and dysfunctional response to OS. Clinically, it is characterized by progressive bone marrow failure, which remains the primary cause of morbidity and mortality. Macrocytosis and increased fetal hemoglobin, two indicators of bone marrow stress erythropoiesis, are generally the first hematological manifestations to appear in FA. However, the significance of RDW and its possible relation to stress erythropoiesis have never been explored in FA. In the present study we analyzed routine complete blood counts from 34 FA patients and evaluated RDW, correlating with the hematological parameters most consistently associated with the FA phenotype.ResultsWe showed, for the first time, that RDW is significantly increased in FA. We also showed that increased RDW is correlated with thrombocytopenia, neutropenia and, most importantly, highly correlated with anemia. Analyzing sequential hemograms from 3 FA patients with different clinical outcomes, during 10 years follow-up, we confirmed a consistent association between increased RDW and decreased hemoglobin, which supports the postulated importance of RDW in the evaluation of hematological disease progression.ConclusionsThis study shows, for the first time, that RDW is significantly increased in FA, and this increment is correlated with neutropenia, thrombocytopenia, and highly correlated with anemia. According to the present results, it is suggested that increased RDW can be a novel marker of stress erythropoiesis in FA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0485-0) contains supplementary material, which is available to authorized users.

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