Treatment of transfusion‐dependent congenital dyserythropoietic anemia Type I patients with pegylated interferon alpha‐2a

Abu‐Quider, Abed; Asleh, Mahdi; Shalev, Hanna; Fruchtman, Yariv; Ben‐Harosh, Meriam; Beck, Guy; Kapelushnik, Josef

doi:10.1111/ejh.13428

Cited by 3 publications

(3 citation statements)

References 19 publications

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“…Most transplants for CDA are performed in childhood (median age is 5.1 years) [68], although adult CDA patients have also successfully undergone bone marrow transplantation [80]. Except for Interferon alpha-2a, which was serendipitously found to reduce/halt hemolysis in CDA I by a yet unknown mechanism [37–41,42 ▪ ], there are no specific therapies for the CDAs, which reflects our poor understanding of the pathogenic mechanisms underlying these disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Several reports have shown improvement in the CDA I anemia with interferon treatment [37–41]. A recent cohort of CDA I patients showed that six out of seven patients achieved transfusion independence with pegylated interferon alpha-2a [42 ▪ ]. Notably, patients treated with pegylated interferon alpha-2a appear to have reduced hemolysis but continue to have high ferritin levels.…”

Section: Congenital Dyserythropoietic Anemia Type Imentioning

confidence: 99%

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The congenital dyserythropoieitic anemias: genetics and pathophysiology

King

Gallagher

Khoriaty

2021

Current Opinion in Hematology

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Purpose of reviewThe congenital dyserythropoietic anemias (CDA) are hereditary disorders characterized by ineffective erythropoiesis. This review evaluates newly developed CDA disease models, the latest advances in understanding the pathogenesis of the CDAs, and recently identified CDA genes.Recent findingsMice exhibiting features of CDAI were recently generated, demonstrating that Codanin-1 (encoded by Cdan1) is essential for primitive erythropoiesis. Additionally, Codanin-1 was found to physically interact with CDIN1, suggesting that mutations in CDAN1 and CDIN1 result in CDAI via a common mechanism. Recent advances in CDAII (which results from SEC23B mutations) have also been made. SEC23B was found to functionally overlap with its paralogous protein, SEC23A, likely explaining the absence of CDAII in SEC23B-deficient mice. In contrast, mice with erythroid-specific deletion of 3 or 4 of the Sec23 alleles exhibited features of CDAII. Increased SEC23A expression rescued the CDAII erythroid defect, suggesting a novel therapeutic strategy for the disease. Additional recent advances included the identification of new CDA genes, RACGAP1 and VPS4A, in CDAIII and a syndromic CDA type, respectively.SummaryEstablishing cellular and animal models of CDA is expected to result in improved understanding of the pathogenesis of these disorders, which may ultimately lead to the development of new therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Congenital Dyserythropoietic Anemia Type Imentioning

confidence: 99%

The congenital dyserythropoieitic anemias: genetics and pathophysiology

King

Gallagher

Khoriaty

2021

Current Opinion in Hematology

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“…Ultra-structural erythroid features include “spongy” heterochromatin (“Swiss cheese type”), enlargement of the nuclear pores and invagination of the nuclear membrane. For some patients, administration of interferon-α (INF-α) improves anemia and normalizes erythroid morphology ( Lavabre-Bertrand et al, 2004 ; Abu-Quider et al, 2020 ), although this treatment has significant toxicities.…”

Section: Introductionmentioning

confidence: 99%

Cdan1 Is Essential for Primitive Erythropoiesis

et al. 2021

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Congenital dyserythropoietic anemia type I (CDA I) is an autosomal recessive disease characterized by moderate to severe macrocytic anemia and pathognomonic morphologic abnormalities of the erythroid precursors, including spongy heterochromatin. The disease is mainly caused by mutations in CDAN1 (encoding for Codanin-1). No patients with homozygous null type mutations have been described, and mouse null mutants die during early embryogenesis prior to the initiation of erythropoiesis. The cellular functions of Codanin-1 and the erythroid specificity of the phenotype remain elusive. To investigate the role of Codanin-1 in erythropoiesis, we crossed mice carrying the Cdan1 floxed allele (Cdanfl/fl) with mice expressing Cre-recombinase under regulation of the erythropoietin receptor promoter (ErGFPcre). The resulting CdanΔEry transgenic embryos died at mid-gestation (E12.5–E13.5) from severe anemia, with very low numbers of circulating erythroblast. Transmission electron microscopy studies of primitive erythroblasts (E9.5) revealed the pathognomonic spongy heterochromatin. The morphology of CdanΔEry primitive erythroblasts demonstrated progressive development of dyserythropoiesis. Annexin V staining showed increases in both early and late-apoptotic erythroblasts compared to controls. Flow cytometry studies using the erythroid-specific cell-surface markers CD71 and Ter119 demonstrated that CdanΔEry erythroid progenitors do not undergo the semi-synchronous maturation characteristic of primitive erythroblasts. Gene expression studies aimed to evaluate the effect of Cdan1 depletion on erythropoiesis revealed a delay of ζ to α globin switch compared to controls. We also found increased expression of Gata2, Pu.1, and Runx1, which are known to inhibit terminal erythroid differentiation. Consistent with this data, our zebrafish model showed increased gata2 expression upon cdan1 knockdown. In summary, we demonstrated for the first time that Cdan1 is required for primitive erythropoiesis, while providing two experimental models for studying the role of Codanin-1 in erythropoiesis and in the pathogenesis of CDA type I.

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