Impaired formation of erythroblastic islands is associated with erythroid failure and poor prognosis in a significant proportion of patients with myelodysplastic syndromes

Buesche, Guntram; Teoman, Huesniye; Giagounidis, Aristoteles; Göhring, Gudrun; Schlegelberger, Brigitte; Ganser, Arnold; Aul, Carlo; Kreipe, Hans-Heinrich

doi:10.3324/haematol.2015.129015

“…Recovery from erythropoietic stress is impaired when macrophages are defective ( Chow et al, 2013 ; Jacobsen et al, 2015 ; Liao et al, 2018 ; May and Forrester, 2020 ; Ramos et al, 2013 ; Sadahira et al, 2000 ), supporting a physiological role for island macrophages in erythroid biology. Altered islands are associated with poor prognosis of myelodysplastic patients ( Buesche et al, 2016 ). Although studies suggest that even an 80% decrease in mouse resident macrophage levels still enables a normal recovery from stress ( Ulyanova et al, 2016 ), this response is effectively aided by differentiation of monocytes to macrophages after recruitment to the splenic red pulp ( Liao et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

EKLF/KLF1 expression defines a unique macrophage subset during mouse erythropoiesis

Mukherjee

¹

,

Xue

²

,

Planutis

³

et al. 2021

eLife

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Erythroblastic islands are a specialized niche that contain a central macrophage surrounded by erythroid cells at various stages of maturation. However, identifying the precise genetic and transcriptional control mechanisms in the island macrophage remains difficult due to macrophage heterogeneity. Using unbiased global sequencing and directed genetic approaches focused on early mammalian development, we find that fetal liver macrophage exhibit a unique expression signature that differentiates them from erythroid and adult macrophage cells. The importance of EKLF/KLF1 in this identity is shown by expression analyses in EKLF-/- and in EKLF-marked macrophage cells. Single cell sequence analysis simplifies heterogeneity and identifies clusters of genes important for EKLF-dependent macrophage function and novel cell surface biomarkers. Remarkably, this singular set of macrophage island cells appears transiently during embryogenesis. Together these studies provide a detailed perspective on the importance of EKLF in establishment of the dynamic gene expression network within erythroblastic islands in the developing embryo and provide the means for their efficient isolation.

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“…With age, the number of erythroid islands in the bone marrow decreases, while their size increases, which may suggest that the decrease in stem cell numbers and erythroid progenitors during aging might be compensated by an increased proliferation of local erythroid progenitors ( Figure 3 ). 60 In patients with MDS, impaired formation of erythroid islands as well as structural abnormalities within these islands have also been described ( Figure 3 ). 60 In low-risk MDS, abnormal formation of erythroid islands may be the only histopathological change found in the bone marrow.…”

Section: Erythropoiesismentioning

confidence: 96%

“… 60 In patients with MDS, impaired formation of erythroid islands as well as structural abnormalities within these islands have also been described ( Figure 3 ). 60 In low-risk MDS, abnormal formation of erythroid islands may be the only histopathological change found in the bone marrow. Moreover, it has been described that erythroid island density correlates inversely with overall survival in patients with MDS.…”

Section: Erythropoiesismentioning

confidence: 96%

“…Moreover, it has been described that erythroid island density correlates inversely with overall survival in patients with MDS. 60 However, alterations of island con figuration and size (e.g. increased size) can also be detected when an increase in red cell production is required in pathological conditions, such as in hemolytic anemia or acute blood loss.…”

Section: Erythropoiesismentioning

confidence: 99%

See 1 more Smart Citation

Normal and pathological erythropoiesis in adults: from gene regulation to targeted treatment concepts

Valent

¹

,

Büsche

²

,

Theurl

³

et al. 2018

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Pathological erythropoiesis with consequent anemia is a leading cause of symptomatic morbidity in internal medicine. The etiologies of anemia are complex and include reactive as well as neoplastic conditions. Clonal expansion of erythroid cells in the bone marrow may result in peripheral erythrocytosis and polycythemia but can also result in anemia when clonal cells are dysplastic and have a maturation arrest that leads to apoptosis and hinders migration, a constellation typically seen in the myelodysplastic syndromes. Rarely, clonal expansion of immature erythroid blasts results in a clinical picture resembling erythroid leukemia. Although several mechanisms underlying normal and abnormal erythropoiesis and the pathogenesis of related disorders have been deciphered in recent years, little is known about specific markers and targets through which prognosis and therapy could be improved in anemic or polycythemic patients. In order to discuss new markers, targets and novel therapeutic approaches in erythroid disorders and the related pathologies, a workshop was organized in Vienna in April 2017. The outcomes of this workshop are summarized in this review, which includes a discussion of new diagnostic and prognostic markers, the updated WHO classification, and an overview of new drugs used to stimulate or to interfere with erythropoiesis in various neoplastic and reactive conditions. The use and usefulness of established and novel erythropoiesis-stimulating agents for various indications, including myelodysplastic syndromes and other neoplasms, are also discussed.

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“…Recovery from erythropoietic stress is impaired when macrophages are defective (Chow et al, 2013;Jacobsen et al, 2015;Liao et al, 2018;May and Forrester, 2020;Ramos et al, 2013;Sadahira et al, 2000), supporting a physiologic role for island macrophages in erythroid biology. Altered islands are associated with poor prognosis of myelodysplastic patients (Buesche et al, 2016). Although studies suggest that even an 80% decrease in mouse resident macrophage levels still enable a normal recovery from stress (Ulyanova et al, 2016), this response is effectively aided by differentiation of monocytes to macrophages after recruitment to the splenic red pulp (Liao et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

EKLF/KLF1 expression defines a unique macrophage subset during mouse erythropoiesis

Mukherjee

¹

,

Xue

²

,

Planutis

³

et al. 2020

Preprint

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Erythroblastic islands are a specialized niche that contain a central macrophage surrounded by erythroid cells at various stages of maturation. However, identifying the precise genetic and transcriptional control mechanisms in the island macrophage remains difficult due to macrophage heterogeneity. Using unbiased global sequencing and directed genetic approaches focused on early mammalian development, we find that fetal liver macrophage exhibit a unique expression signature that differentiates them from erythroid and adult macrophage cells. The importance of EKLF/KLF1 in this identity is shown by expression analyses in EKLF-/- and in EKLF-marked macrophage cells. Single cell sequence analysis simplifies heterogeneity and identifies clusters of genes important for EKLF-dependent macrophage function and novel cell surface biomarkers. Remarkably, this singular set of macrophage island cells appears transiently during embryogenesis. Together these studies provide a detailed perspective on the importance of EKLF in establishment of the dynamic gene expression network within erythroblastic islands in the developing embryo and provide the means for their efficient isolation.

show abstract

Impaired formation of erythroblastic islands is associated with erythroid failure and poor prognosis in a significant proportion of patients with myelodysplastic syndromes

Cited by 13 publications

References 11 publications

EKLF/KLF1 expression defines a unique macrophage subset during mouse erythropoiesis

EKLF/KLF1 expression defines a unique macrophage subset during mouse erythropoiesis

Normal and pathological erythropoiesis in adults: from gene regulation to targeted treatment concepts

EKLF/KLF1 expression defines a unique macrophage subset during mouse erythropoiesis

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