KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells

Kohara, Hiroshi; Utsugisawa, Taiju; Sakamoto, Chika; Hirose, Lisa; Ogawa, Yoshiaki; Ogura, Hiromi; Sugawara, Ai; Liao, Jiyuan; Aoki, Takako; Iwasaki, Takanori; Asai, Takayoshi; Doisaki, Sayoko; Muramatsu, Hideki; Abe, Takaaki; Kurita, Ryo; Miyamoto, Shohei; Sakuma, Tetsushi; Shiba, Masayuki; Yamamoto, Takashi; Ohga, Shouichi; Yoshida, Kenichi; Ogawa, Seishi; Ito, Etsuro; Kojima, Seiji; Kanno, Hitoshi; Tani, Kenzaburo

doi:10.1016/j.exphem.2019.03.001

Cited by 20 publications

(20 citation statements)

References 46 publications

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“…Macrophages and RBCs differentiated from patient-derived iPSCs would allow for the in vitro modeling of EBIs in disease and could prove especially useful for dissecting the contributions of each cell type to disease pathology. 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].…”

Section: Monocyte-derived Macrophagessupporting

confidence: 61%

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: 61%

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

May

Forrester

2020

Experimental Hematology

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“…Since we did not have access to CDA type IV patients as this disease is very rare and as only seven cases have been described (26,27,(30)(31)(32)(33)(34)(35)(36)(37)(38), we prepared stable K562 cell lines with doxycycline-inducible expression constructs of WT-KLF1 or CDA-KLF1. We investigated the level of transcription for known KLF1 target genes, which have both types of binding sites for the WT-and CDA-KLF1 variants in their regulatory regions (promoters and/or introns).…”

Section: Discussionmentioning

confidence: 99%

“…First, it is known that AQP1 levels are dramatically lower in samples originating from patients suffering from CDA type IV than in those of healthy controls (16,36,55). Second, expression of EPB4.2 is reduced in CDA induced pluripotent stem cell (iPS)-derived erythroblasts (38); also, analysis of the transcriptome of the CDA patient revealed its decreased level, as it contributes to the fragility of CDA patients' red cell membrane abnormalities (56). Third, expression of the 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: Figmentioning

confidence: 99%

“…Fourth, expression of E2F2 is decreased in the presence of the Nan-KLF1 mutation (25). Finally, the Cdkn1B gene (p27 gene) is directly regulated by KLF1 during late stages of differentiation, where it is critical for enucleation of erythroid precursors (57), and this process is disturbed in the presence of CDA mutation (38,56). Furthermore, we expanded our analysis for TFR2 (for transferrin receptor 2), SLC4A1 (for anion transport protein; BAND3), and IL17RB (for interleukin-17 receptor B) based on a recently published article (56).…”

Section: Figmentioning

confidence: 99%

“…To date, only seven patients suffering from CDA type IV have been described (26,27,(30)(31)(32)(33)(34)(35)(36)(37)(38). In general, CDAs are a heterogeneous group of rare hereditary diseases.…”

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confidence: 99%

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A Krüppel-like factor 1 (KLF1) Mutation Associated with Severe Congenital Dyserythropoietic Anemia Alters Its DNA-Binding Specificity

Kulczyńska

Bieker

Siatecka

2020

Molecular and Cellular Biology

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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-cell-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 vivo functional reporter gene studies. Two significant changes compared to wild-type (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 effects on erythroid physiology in CDA type IV.

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Congenital dyserythropoietic anemia type IV in the genetic era: A rare neonatal case report of rapid identification with a review of the literature

Deguise

Blain

Simpson

et al. 2023

Pediatric Blood & Cancer

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Congenital dyserythropoietic anemia type IV (CDAIV) is a rare inherited hematological disorder, presenting with severe anemia due to altered erythropoiesis and hemolysis, with variable needs for recurrent transfusions. We present a case of a transfusiondependent male newborn who presented at birth with severe hemolytic anemia, and required an intrauterine transfusion. Genetic testing rapidly identified a Kruppel-like factor 1 (KLF1) pathogenic variant (c.973G>A, p.E325K), known to be causative for CDAIV. This case highlights the advantages of next-generation sequencing testing for congenital hemolytic anemia: diagnostic speed, guidance on natural history, and optimized clinical management and anticipatory guidance for parents and clinicians.Additionally, we reviewed the literature for all CDAIV cases.

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KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells

Cited by 20 publications

References 46 publications

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

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

A Krüppel-like factor 1 (KLF1) Mutation Associated with Severe Congenital Dyserythropoietic Anemia Alters Its DNA-Binding Specificity

Congenital dyserythropoietic anemia type IV in the genetic era: A rare neonatal case report of rapid identification with a review of the literature

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