A variant erythroferrone disrupts iron homeostasis in SF3B1 -mutated myelodysplastic syndrome

Abstract

Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in theSF3B1splicing factor gene. Patients with MDS withSF3B1mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for erythropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternativeERFEtranscript in patients with MDS with theSF3B1mutation. Induction of thisERFEtranscript in primarySF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with anSF3B1gene mutation than in patients withSF3B1wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients withSF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variantERFEtranscript that was restricted toSF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.

SF3B1-mutant MDS as a distinct disease subtype: a proposal from the International Working Group for the Prognosis of MDS

“…16,25 In addition, it is also possible that NMD-insensitive aberrant transcripts are translated into aberrant proteins with altered function. 16,25,26 Two genes involved in mitochondrial iron metabolism synthesis, PPOX and ABCB7, were found to be significantly downregulated in SF3B1-mutated samples. As PPOX encodes protoporphyrinogen oxidase, which catalyzes the dehydrogenation of protoporphyrinogen IX to form protoporphyrin IX, it is likely that haploinsufficiency of this gene may induce defective heme synthesis and iron accumulation into the mitochondria.…”

“…SF3B1-mutant patients have a high degree of ineffective hematopoiesis that results in elevated erythroferrone levels and inappropriately low serum hepcidin, as typically observed in congenital iron-loading anemias due to ineffective erythropoiesis. 26,49 Transforming growth factor-b superfamily ligand traps have been found to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis in animal models of ineffective erythropoiesis. [50][51][52] Luspatercept is a recombinant fusion protein that binds transforming growth factor-b superfamily ligands to reduce Smad2/3 signaling.…”

Human Cancer-Associated Mutations of SF3B1 Lead to a Splicing Modification of Its Own RNA

“…SF3B1 mutant cells are expected to accumulate numerous other aberrant proteins, which could participate in carcinogenesis. So far, to our knowledge, only two studies dealt with the neoproteins specifically produced in SF3B1 mutated cells ( [28] and this work). Significant progress is expected in the characterization of these splicing-derived cancer specific proteins in order to propose novel biomarkers and therapeutic options.…”

“…By exploring publicly available RNA-seq raw data obtained from patients with SF3B1 mutations, we identified a transcript of SF3B1 that was solely detected in SF3B1 mutated samples in various neoplasms, including breast cancer [16], uveal melanoma [19] and recently in MDS [28]. This transcript, which we named SF3B1ins, results from the retention of 24 nucleotides from intron 12 into exon 13, through the recognition of a cryptic AG' 3' splice site located 24 nucleotides upstream of the canonical AG 3' splice site ( Figure 1A).…”

From Iron Chelation to Overload as a Therapeutic Strategy to Induce Ferroptosis in Leukemic Cells

“…Notably however, despite the expected high levels of hepcidin under conditions of inflammation and overexpression of ferritin, balancing strategies to counteract anemia such as erythroblast secretion of erythroferrone (ERFE) can foster hepcidin downregulation ( 45 ). An example of this is seen in myelodysplastic syndromes with an SF3B1 mutation ( 46 ). In response to systemic limitations in iron availability, autocrine secretion of hepcidin to degrade FPN has been described in several cancer models, although not yet shown in AML ( 47 – 49 ).…”