Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient

Varricchio, Lilian; Planutis, Antanas; Manwani, Deepa; Jaffray, Julie; Mitchell, W. Beau; Migliaccio, Anna Rita; Bieker, James J.

doi:10.3324/haematol.2018.209858

Cited by 19 publications

(20 citation statements)

References 69 publications

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“…By use of an iPSC line derived from a CDA patient, it was shown that the KLF1-E325K mutation induces cell cycle arrest in differentiated erythroid cells [116]. This was comparable to data derived from erythroid cells differentiated from patient-derived CD34+ progenitors where RNA sequencing revealed the dysregulation of cell cycle genes [117]. In the future, the production of macrophages from this patientderived iPSC line will elucidate whether the presence of the KLF1-E325K mutant protein in the EBI niche contributes to the pathology of the disease and will determine whether targeting the niche might be a therapeutic option.…”

Section: Monocyte-derived Macrophagessupporting

confidence: 60%

The erythroblastic island niche: modeling in health, stress, and disease

May

Forrester

2020

Experimental Hematology

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Erythropoiesis is one of the most demanding processes in the body, with more than 2 million red blood cells produced every second. Multiple hereditary and acquired red blood cell disorders arise from this complex system, with existing treatments effective in managing some of these conditions but few offering a long-term cure. Finding new treatments relies on the full understanding of the cellular and molecular interactions associated with the production and maturation of red blood cells, which take place within the erythroblastic island niche. The elucidation of processes associated within the erythroblastic island niche in health and during stress erythropoiesis has relied on in vivo modeling in mice, with complexities dissected using simple in vitro systems. Recent progress using state-of-the-art stem cell technology and gene editing has enabled a more detailed study of the human niche. Here, we review these different models and describe how they have been used to identify and characterize the cellular and molecular pathways associated with red blood cell production and maturation. We speculate that these systems could be applied to modeling red blood cell diseases and finding new druggable targets, which would prove especially useful for patients resistant to existing treatments. These models could also aid in research into the manufacture of red blood cells in vitro to replace donor blood transfusions, which is the most common treatment of blood disorders.

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Section: Monocyte-derived Macrophagessupporting

confidence: 60%

The erythroblastic island niche: modeling in health, stress, and disease

May

Forrester

2020

Experimental Hematology

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“…It will be of interest to analyze the transcriptome of CDA type IV patients to verify that they indeed have ectopic expression of neomorphic, CDA-KLF1 activated genes. A recent study (55) shows that the genomic regions surrounding a number of the top ectopically expressed genes in a CDA patient (36) contain sites that, based on the present study, bind and are activated by CDA-KLF1 (5'-TGG-GGG-TGG-3' (Fig. 1 and 7)).…”

Section: Discussionsupporting

confidence: 65%

“…1 and 7)). We tested some of them and the higher level of expression from CDA-KLF1 we obtained for IL17RB, that is critical for expression of IL8 (55). Since the genes activation by CDA-KLF1 were not confirmed by ChIP assay, we may not exclude the indirect effect of the presence of KLF1 mutant.…”

Section: Discussionmentioning

confidence: 99%

“…Our rationale was as follows: first, it is known that AQP1 levels are dramatically lower in samples originating from patients suffering from CDA type IV compared to healthy controls (16,35,54). Expression of EPB4.2 is reduced in CDA-iPS-derived erythroblasts (37) also analysis of transcriptome of the CDA patient revealed it decreased level, as it contributes to the fragility of CDA patients' red cells membrane abnormalities (55). Second, expression of BCAM gene is lower in individuals with the In(Lu) phenotype that is caused by a variety of KLF1 mutations that lead to its haploinsufficiency (18).…”

Section: Quantitative Analysis Of the Endogenous Levels Of Klf1 Targementioning

confidence: 99%

“…Finally, the Cdkn1B gene (p27) is directly regulated by KLF1 during late stages of differentiation, where it is critical for enucleation of erythroid precursors (56) and this process is disturbed in the presence of CDA mutation (37,55). Furthermore, we expanded our analysis for TFR2transferrin receptor 2, SLC4A1-anion transport protein (BAND3) and IL17RB-Interleukin-17 receptor B based on recently published article (55).…”

Section: Quantitative Analysis Of the Endogenous Levels Of Klf1 Targementioning

confidence: 99%

See 2 more Smart Citations

AKrüppel-like factor 1(KLF1) mutation associated with severe congenital dyserythropoietic anemia alters its DNA-binding specificity

Kulczyńska

Bieker

Siatecka

2019

Preprint

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Krüppel-like factor 1 (KLF1/EKLF) is a transcription factor that globally activates genes involved in erythroid cell development. Various mutations are identified in the human KLF1 gene. The E325K mutation causes congenital dyserythropoietic anemia (CDA) type IV, characterized by severe anemia and non-erythroid-related symptoms. The CDA mutation is in the second zinc finger of KLF1 at a position functionally involved in its interactions with DNA. The molecular parameters of how CDA-KLF1 exerts its biological effects have not been addressed. Here, using an in vitro selection strategy we determined the preferred DNA-binding site for CDA-KLF1. Binding to the deduced consensus sequence is supported by in vitro gel shifts and by in vivofunctional reporter gene studies. Two significant changes compared to WT binding are observed: G is selected as the middle nucleotide and the 3'-portion of the consensus sequence is more degenerate. As a consequence CDA-KLF1 did not bind the WT consensus sequence. However, activation of ectopic sites is promoted. Continuous activation of WT target genes occurs if they fortuitously contain the novel CDA site nearby. Our findings provide a molecular understanding of how a single mutation in the KLF1 zinc finger exerts an effects on erythroid physiology in CDA type IV.

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Erythroid Krüppel-Like Factor (KLF1): A Surprisingly Versatile Regulator of Erythroid Differentiation

Bieker,

Philipsen

2024

Transcription Factors in Blood Cell Development

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Genetic disarray follows mutant KLF1-E325K expression in a congenital dyserythropoietic anemia patient

Cited by 19 publications

References 69 publications

The erythroblastic island niche: modeling in health, stress, and disease

The erythroblastic island niche: modeling in health, stress, and disease

AKrüppel-like factor 1(KLF1) mutation associated with severe congenital dyserythropoietic anemia alters its DNA-binding specificity

Erythroid Krüppel-Like Factor (KLF1): A Surprisingly Versatile Regulator of Erythroid Differentiation

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