Dyserythropoiesis of myelodysplastic syndromes

Lefevre, Carine; Bondu, Sabrina; Goff, Salomé Le; Kosmider, Olivier; Fontenay, Michaëla

doi:10.1097/moh.0000000000000325

Cited by 22 publications

(22 citation statements)

References 66 publications

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“…Defects in chromatin condensation in the erythroid lineage are commonly seen in patients with megaloblastic anemia and myelodysplastic syndromes (MDS) . The pathogenesis of these defects is not clear.…”

Section: Resultsmentioning

confidence: 99%

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Disruption of erythroid nuclear opening and histone release in myelodysplastic syndromes

et al. 2019

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Mammalian terminal erythropoiesis involves several characteristic phenomena including chromatin condensation and enucleation. One of the newly identified features of terminal erythropoiesis in mouse is a dynamic nuclear opening and histone release process, which is required for chromatin condensation. However, it is unclear whether the same feature is present in human. Here, we use an in vitro human CD34‐positive hematopoietic stem and progenitor cell culture system and reveal that nuclear openings and histone release are also identified during human terminal erythropoiesis. In contrast to mouse in which each erythroblast contains a single opening, multiple nuclear openings are present in human erythroblast, particularly during the late‐stage differentiation. The nuclear opening and histone release process is mediated by caspase‐3. Inhibition of caspase‐3 blocks nuclear opening, histone release, chromatin condensation, and terminal differentiation. We confirm the finding of histone cytosolic release in paraffin‐embedded human bone marrow in vivo. Importantly, we find that patients with myelodysplastic syndrome (MDS) exhibit significant defects in histone release in the dysplastic erythroblasts. Our results reveal developmentally conserved nuclear envelop and histone dynamic changes in human terminal erythropoiesis and indicate that disruption of the histone release process plays a critical role in the pathogenesis of dyserythropoiesis in MDS.

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Section: Resultsmentioning

confidence: 99%

“…Erythroid dysplasia is one of the hallmark features of MDS. Dyserythropoiesis is found in more than 80% of early‐stage MDS . Nuclear changes like abnormal chromatin clumping, bi/multinuclearity or nuclear bridges are features of erythroid cell dysplasia .…”

Section: Discussionmentioning

confidence: 99%

Disruption of erythroid nuclear opening and histone release in myelodysplastic syndromes

et al. 2019

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“…To be diagnosed with MDS, one has to have dysplastic cells in excess of 10% [ 16 , 17 , 18 ]. In cases with low-grade dysplasia or no dysplasia, other potential causes of cytopenia should be excluded [ 19 ].…”

Section: Mds Classificationmentioning

confidence: 99%

Prognostic Markers of Myelodysplastic Syndromes

et al. 2020

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Myelodysplastic syndrome (MDS) is a clonal disease characterized by multilineage dysplasia, peripheral blood cytopenias, and a high risk of transformation to acute myeloid leukemia. In theory, from clonal hematopoiesis of indeterminate potential to hematologic malignancies, there is a complex interplay between genetic and epigenetic factors, including miRNA. In practice, karyotype analysis assigns patients to different prognostic groups, and mutations are often associated with a particular disease phenotype. Among myeloproliferative disorders, secondary MDS is a group of special entities with a typical spectrum of genetic mutations and cytogenetic rearrangements resembling those in de novo MDS. This overview analyzes the present prognostic systems of MDS and the most recent efforts in the search for genetic and epigenetic markers for the diagnosis and prognosis of MDS.

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“…In some cases, the number of RBCs is extremely low because of the failure to produce erythroid progenitors, as in Diamond-Blackfan Anemia (DBA) (Da Costa et al, 2018). In other cases, impaired differentiation leads to the accumulation of erythroid precursors in the bone marrow [β-thalassemia (Rivella, 2015), congenital dyserythropoietic anemia, CDA (Iolascon et al, 2011)] or to the unbalanced production of different blood cell types [myelodysplastic syndromes, MDS (Levine et al, 2007; Lefevre et al, 2017)], resulting in insufficient RBC numbers in the bloodstream. In other forms of anemias, RBCs are produced but defects in some crucial gene products [typically specific enzymes (Koralkova et al, 2014; Grace et al, 2018), membrane proteins or cytoskeletal components (Mohandas and Gallagher, 2008; Perrotta et al, 2008), sickle globin chains (Rees et al, 2010), channel proteins (Glogowska and Gallagher, 2015), specific pathways (Bianchi et al, 2009; Schwarz et al, 2009)] result in RBCs with decreased oxygen delivery capacity and/or shortened lifespan.…”

Section: Introductionmentioning

confidence: 99%

The Pleiotropic Effects of GATA1 and KLF1 in Physiological Erythropoiesis and in Dyserythropoietic Disorders

2019

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In the last few years, the advent of new technological approaches has led to a better knowledge of the ontogeny of erythropoiesis during development and of the journey leading from hematopoietic stem cells (HSCs) to mature red blood cells (RBCs). Our view of a well-defined hierarchical model of hematopoiesis with a near-homogeneous HSC population residing at the apex has been progressively challenged in favor of a landscape where HSCs themselves are highly heterogeneous and lineages separate earlier than previously thought. The coordination of these events is orchestrated by transcription factors (TFs) that work in a combinatorial manner to activate and/or repress their target genes. The development of next generation sequencing (NGS) has facilitated the identification of pathological mutations involving TFs underlying hematological defects. The examples of GATA1 and KLF1 presented in this review suggest that in the next few years the number of TF mutations associated with dyserythropoietic disorders will further increase.

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Dyserythropoiesis of myelodysplastic syndromes

Cited by 22 publications

References 66 publications

Disruption of erythroid nuclear opening and histone release in myelodysplastic syndromes

Disruption of erythroid nuclear opening and histone release in myelodysplastic syndromes

Prognostic Markers of Myelodysplastic Syndromes

The Pleiotropic Effects of GATA1 and KLF1 in Physiological Erythropoiesis and in Dyserythropoietic Disorders

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