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Grant Proposal Gattermann 1. Allgemeine Angaben 1.1 Antragsteller - Prof. Dr. Norbert Gattermann, Heinrich-Heine-Universität Düsseldorf - Dr. Mayka Sanchez, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain. 1.2 Thema: Myelodysplastische Syndrome (MDS): Ursache der mitochondrialen Eisenüberladung bei sidero- blastischer Anämie (MDS: Cause of mitochondrial iron overload in sideroblastic anemia). 1.3. Kennwort: MDS: mitochondriale Eisenüberladung 1.4. Fachgebiet und Arbeitsrichtung des Antragstellers: Gattermann: Hämatologie/Onkologie, MDS, Epigenetische Behandlung, Refraktäre Anämie mit Ringsideroblasten (RARS), Mutationen der Mitochondrien-DNA, Eisenüberladung Sanchez: Regulation des Eisenstoffwechsels, IRP/IRE (iron regulatory proteins / iron response elements), Verbindung zwischen Eisenstoffwechsel und Krebsentstehung, Entdeckung neuer Gene mit ursächlicher Bedeutung für Erkrankungen mit gestörter Eisenbilanz. 1.5. Gesamtdauer des Projektes: 3 Jahre 1.6. Förderzeitraum: 01.06.2014 bis 01.06.2017 1.7. Gewünschter Beginn der Förderung: 01.06.2014 2. Abstract Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by dysplasia and ineffective hematopoiesis. A subgroup of patients, namely those with sideroblastic anemia, have abnormal erythroid precursors (ring sideroblasts) showing massive mitochondrial iron accumulation. These subtypes are called “refractory anemia with ring sideroblasts” (RARS), “RARS with thrombocytosis” (RARS-T), and “refractory cytopenia with multilineage dysplasia and ringed sideroblasts” (RCMD-RS). MDS patients with sideroblastic anemia develop systemic iron overload, partly from increased intestinal iron absorption and partly from chronic transfusion therapy. In the majority (60-80%) of patients with RARS and RARS-T, somatic mutations are detectable in SF3B1, a component of the spliceosomal U2snRNP complex. However, the molecular mechanisms by which mutations in SF3B1 lead to mitochondrial iron accumulation are still unclear. To dissect the underlying mechanism in SF3B1 mutated sideroblastic MDS, we will study the cellular iron regulatory system (IRP/IRE system), in particular the possible implications of newly identified mRNAs controlled by this system. Consequences of altered gene expression and altered exon usage will be investigated with regard to the IRP/IRE regulatory system, the iron- sulfur-cluster biogenesis and the cellular iron speciation in MDS patients with sideroblastic anemia. 1 As MDS patients with sideroblastic anemia have a low rate of leukemic transformation, their main problem is chronic anemia. Understanding the mechanism responsible for deranged mitochondrial iron metabolism may lead to novel treatment strategies aimed at more effective erythropoiesis and less iron-related cell and tissue damage. 3. State of the art Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell diseases characterized by dysplasia, ineffective hematopoiesis, and the risk of progression to acute myeloid leukaemia (AML). Shortened survival in MDS patients is due to the consequences of bone marrow failure [1]. Since MDS is an age-related disease, with a median age of 72 years at diagnosis, the prevalence is rising steadily in our aging population. A subgroup of patients have sideroblastic anemia, which is characterized by at least 15% ring sideroblasts in the bone marrow, i.e. pathological erythroblasts showing gross mitochondrial iron accumulation. These cases are classified as refractory anaemia with ring sideroblasts (RARS), RARS with thrombocytosis (RARS-T), and refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). MDS patients with sideroblastic anemia develop systemic iron overload, partly from increased intestinal iron absorption and partly from regular transfusion of red blood cells. Iron overload contributes to shortened survival in these patients [2]. The observation that iron chelation therapy improves erythropoiesis in about 20% of transfusion-dependent MDS patients [3] suggests that iron overlaod aggravates the bone marrow failure in MDS. Recently, whole genome sequencing revealed that spliceosome mutations are detectable in approximately 45% of all MDS patients [4]. In particular, 60-80% of patients with RARS and RARS- T present somatic heterozygous mutations in the SF3B1 gene [5]. SF3B1, splicing factor 3b, subunit 1, is a component of the U2-small nuclear ribonucleoprotein (U2-snRNP) complex needed for normal RNA splicing. Several studies with material from RARS patients as well as an Sf3b1 heterozygous knockout mouse model found a strong correlation between SF3B1 mutations and the sideroblastic phenotype [6-8]. SF3B1 mutations are infrequently found in non-myelodysplastic bone marrow failure, but, if present, are always associated with the presence of ring sideroblasts [9]. Since SF3B1 mutations are an independent predictor of a favourable clinical course, they may be incorporated into risk stratification systems for MDS [8]. It is still unclear how mutant SF3B1 leads to the formation of ring sideroblasts, and some discrepancies remain unresolved. For instance, Boultwood et al [10] showed down-regulated mRNA of the iron-sulphur cluster exporter ABCB7 in patients with RARS, but Visconte et al [6] found no difference in exon-usage or gene expression in ABCB7, a gene mutated in X-linked congenital sideroblastic anemia with ataxia. Mitochondrial iron accumulation can be due to impaired synthesis/export of heme or impaired synthesis/export of iron-sulphur clusters (ISCs). However, the differential usage of exons and the down-regulation of many genes in hematopoietic cells carrying SF3B1mutations have not revealed any obvious gene involved in mitochondrial iron, heme or ISC metabolism that might explain the sideroblastic phenotype. 2 We have hypothesized that SF3B1 mutations may compromise a hitherto unknown physiologic role of SF3B1 in mitochondrial iron metabolism or create a novel, unphysiologic effect on mitochondrial iron handling (Annex 1) [11]. This may involve one or more of the novel mRNAs that were identified by Dr. Sanchez (IJC, Badalona) to be regulated by the iron regulatory proteins IRP1 and IRP2 [12]. Cellular iron homeostasis is controlled post-transcriptionally by the IRP/IRE regulatory system[13]. The iron-regulatory proteins (IRP1 and IRP2) can recognize cis-regulatory mRNA motifs called iron-responsive elements (IREs), i.e. conserved RNA elements located in the untranslated regions (UTR) of mRNAs that encode proteins involved in iron metabolism (TFR1, DMT1, ferritin L and H, ferroportin, ACO2 and ALAS2)[13]. IRP1 and IRP2 IRE binding activities are regulated by iron, and IRPs only bind to IREs under iron-limited conditions. IRP1 is a dual-function protein that acts as aconitase when containing an iron-sulfur cluster (ISC) in iron replenished conditions, whereas it shows IRE-binding activity when intra-cytoplasmatic levels of iron are low. IRP2 is degraded in the presence of high cytoplasmatic iron levels by a proteosomal E3 ubiquitin ligase complex containing the FBXL5 protein, a protein that itself requires iron and oxygen for its function. Heme has been also implicated in the degradation of IRP2[14]. Both IRPs inhibit translation initiation when bound to 5’UTR IREs, while their association with the 3’UTR IREs of the TFR1 mRNA decreases its turnover by preventing mRNA degradation via an as yet unidentified endoribonuclease. Disruption of both copies of the IRP1 and the IRP2 genes in mice is embryonic lethal, indicating that the IRP/IRE regulatory network is essential[15]. While IRP1-deficient mice display no overt phenotype in steady state conditions, IRP2 knock-out mice develop mild microcytic hypochromic anemia with altered body iron distribution[16], and mice with an inducible gain of IRP1 function show abnormal body iron distribution and erythropoiesis[17]. A defect in ISC biosynthesis/export or in the heme pathway will affect the IRE binding activity of IRP1 and IRP2. Indeed, abnormally high IRP1-IRE activity has been found in patients affected by congenital sideroblastic anaemia (CSA) linked to deficiency of GLRX5 (glutaredoxin 5 plays a role in ISC assembly)[18]. Furthermore, the expression of ALAS2 (aminolevulinic acid synthase), which is mutated in X-linked CSA, is controlled by the IRP/IRE system[19]. These findings in congenital sideroblastic anemias suggest that the IRP/IRE regulatory system may also be disrupted in MDS-related sideroblastic anemia. As this hypothesis has not been adequately studied to date, we wish to test it in the proposed project (see objective 1). Recent discoveries by Dr. Sanchez led to the identification of novel mRNAs that can bind IRPs. Using a high-throughput genome-wide approach[20], Sanchez et al. defined the whole repertoire of mRNAs regulated by both IRPs [21-23] and identified a cohort of first-time-described IRP1- and IRP2-specific binding mRNAs [23]. In total, 258 mRNAs were found to interact with IRPs (44 mRNAs bind both IRPs, 101 specifically bind IRP1, and 113 specifically bind IRP2), including all 9 known murine IRP-binding mRNAs [23]. These findings generate questions as to the regulation of the novel IRP-target mRNAs via iron-dependent or -independent mechanisms and create new opportunities to investigate the cause of mitochondrial iron overload. Thus, our objective 2 is to 3 explore the role of novel IRP-target mRNAs in the pathophysiology of MDS-related sideroblastic anemia. Since cytokines are important in regulating differentiation of hematopoietic
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