DeCure for Alpha-thalassemia-myelodysplastic syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for alpha-thalassemia-myelodysplastic syndrome — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAlpha-thalassemia-myelodysplastic syndrome maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for alpha-thalassemia-myelodysplastic syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
ATRX chromatin remodeler (ATRX) — ATRX is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9L06 · 3.4 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
Acquired alpha-thalassaemia in myelodysplastic syndrome is a distinct entity where the haemoglobin defect arises in the neoplastic clone, not from inheritance. Two molecular mechanisms are recognised: deletion of the alpha-globin gene cluster limited to the malignant clone, and, more commonly, inactivating somatic mutations of the trans-acting chromatin factor ATRX that down-regulate alpha-globin expression. The condition is almost always associated with myelodysplastic syndrome. A 2024 report identified a novel 145 kb deletion (Guigang deletion) in the alpha-globin cluster from a Chinese newborn with Hb Bart’s 3.0%, but this was a germline finding, not acquired MDS.
In a 2014 case series of nine patients with alpha or beta thalassaemic trait who developed MDS, median age was 80 years (range 66–89). Subtypes were refractory anaemia without sideroblasts (four cases), refractory cytopenia with multilineage dysplasia (three cases), and refractory anaemia with excess blasts-1 (two cases). Blast percentages ranged from 1% to 7%. Cytogenetic abnormalities included Y chromosome loss (two patients), 20q12 deletion (one patient), and trisomy 8 (one patient); five patients had no detectable karyotypic changes. Seven patients had low-risk MDS by International Prognostic Scoring System, two had intermediate-1 disease. Six patients were treated with recombinant human erythropoietin; all treated patients achieved transfusion independence. After median follow-up of 19 months (range 2–36), no progression to acute myeloid leukaemia was observed. The authors note that standard prognostic systems may overestimate risk in these patients because their baseline haemoglobin is already low from thalassaemia.
A 2017 case report describes a 59-year-old man with presumed beta-thalassaemia intermedia who developed worsening anaemia. Bone marrow showed erythroid hyperplasia and dysplasia with ring sideroblasts >15%, plus mild myeloid and megakaryocytic dysplasia. Molecular analysis revealed SF3B1 and TET2 mutations, consistent with MDS with ring sideroblasts. A 2004 review notes that acquired alpha-thalassaemia in MDS is the best characterised acquired red cell disorder in haematologic malignancy. A 2011 case report describes a 10-year-old girl with beta-thalassaemia intermedia and myelofibrosis, but this is beta-thalassaemia, not alpha, and the association with MDS is not established in that report.
What is missing: prospective studies that define the natural history of MDS arising in alpha-thalassaemia carriers, validated prognostic systems that account for pre-existing low haemoglobin, and trials testing whether erythropoietin or other agents alter progression. The distinction between true MDS and severe dyserythropoiesis from thalassaemic stress remains unresolved.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 2004 · 108 citations · open access
Acquired α-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies
AbstractAbnormalities of hemoglobin synthesis are usually inherited but may also arise as a secondary manifestation of another disease, most commonly hematologic neoplasia. Acquired hemoglobin disorders can be seen in any population and are not restricted to areas of the world with high incidences of inherited hemoglobinopathies. In fact, the acquired hemoglobinopathies may be more readily recognized where inherited hemoglobin abnormalities are rare and less likely to cause diagnostic confusion. Acquired alpha-thalassemia is the best characterized of the acquired red blood cell disorders in patients with hematologic malignancy, and it is almost always associated with a myelodysplastic syndrome (MDS). At least 2 molecular mechanisms for acquired alpha-thalassemia are now recognized: acquired deletion of the alpha-globin gene cluster limited to the neoplastic clone and, more commonly, inactivating somatic mutations of the trans-acting chromatin-associated factor ATRX, which cause dramatic down-regulation of alpha-globin gene expression. Here we review the clinical, hematologic, and molecular genetic features of alpha-thalassemia arising in a clonal myeloid disorder, and we discuss howATRX might affect gene expression in normal and abnormal hematopoiesis through epigenetic mechanisms.
Journal of Pediatric Hematology/Oncology · 2011 · 5 citations
Myelofibrosis
AbstractA 10-year-old girl presented with gradually increasing pallor and abdominal distension for 1 year and fever for 6 months. She required 3 packed cell transfusions during this interval. Investigations done revealed that the child had thalassemia intermedia and parents were carrier of β-thalassemia gene. The increased transfusion requirement in this case prompted further investigations, which revealed the presence of myelofibrosis. Case reports of myelofibrosis and myelodysplastic syndromes with acquired hemoglobin disorders exist in literature, especially α-thalassemia. To the best of our knowledge, this is the first reported case of β-thalassemia intermedia in association with myelofibrosis.
Identification of a novel 145 kb deletion (Guigang deletion, – <sup>Guigang</sup> ) in the alpha-globin gene cluster from a Chinese newborn using third-generation sequencing
AbstractObjective To describe a novel α-thalassemiadeletion identified from a newborn by third-generation sequencing (TGS).Case report The proband, a newborn subject to neonatal capillary electrophoresis (CE) screening, exhibited suspected α0-thalassemia carrier status (Hb Bart’s 3.0%). Notably, both parents had negative results on thalassemia screening during pregnancy. Multiplex ligation-dependent probe amplification (MLPA) presented a deletion between probes 364nt and 472 nt that extended from the HBZ gene to the downstream region of the RGS11 gene. Subsequently, TGS determined the approximated break position of this deletion, indicating a length exceeding 145 kb (chr16:127,815-273,190 del 145376 bp). Sanger sequencing validated the upstream and downstream breakpoints of this deletion. Only maternal data were available for pedigree analysis, with the father's sample lacking. MLPA showed no deletion in the mother, suggesting possible paternal inheritance. The deletion was named Guigang deletion (--Guigang) after the proband’s city of origin, Guigang.Conclusions We reported a novel α-thalassemiadeletion and provided insights into the hematological phenotype and molecular analysis. These findings have implications for genetic counseling and prenatal diagnosis.
Zenodo (CERN European Organization for Nuclear Research) · 2017 · 2 citations · open access
A Rare Case of Myelodysplastic Syndrome with Ring Sideroblasts, SF3B1 and TET2 Mutations in a Patient with Beta Thalassemia Trait
AbstractConcurrent myelodysplastic syndrome (MDS) and β-thalassemia trait is rare. We reported a case of a 59-year-old man with a known history of β-thalassemia (presumed to be β-thalassemia intermedia) presenting with progressive anemia and worsening fatigue. β-globin mutation analysis revealed a heterozygous mutation in the beta-globin gene, compatible with β-thalassemia trait. Bone marrow biopsy showed erythroid hyperplasia and erythroid dysplasia with increased ring sideroblasts (>15%). Additionally, there is also mild myeloid and megakaryocytic dysplasia. Molecular analysis revealed SF3B1 and TET2 mutations. These findings are consistent with myelodysplastic syndrome with ring sideroblasts (MDS-RS). To the best of our knowledge, this is the first report of MDS-RS with SF3B1 and TET2 mutations in a patient heterozygous for β-globin gene mutation. For β-thalassemia patients with worsening anemia, a comprehensive bone marrow analysis including cytogenetic and molecular studies is important to help further delineate the diagnosis.
Diagnosis of myelodysplastic syndromes in individuals heterozygous for mutations in the α- and β-globin genes: a reminder for haematologists.
AbstractDear Sir,
Concomitant myelodysplastic syndromes (MDS) diagnosed in individuals heterozygous for α- or β-globin gene mutations are rarely reported. However, the development of MDS in subjects carrying a globin gene mutation may result in haematological phenotypes with clinical and laboratory features that can create several diagnostic and therapeutic problems. Given the rarity of this combination of disorders, the characteristic features have not been fully elucidated1. We, therefore, believe that it could be useful to present our data, based on a review of our recent clinical experience, together with our considerations on this neglected topic.
From our database, we retrieved nine cases of patients with an α or β-thalassaemic trait who were diagnosed as having MDS. These patients were under our care because they had cytopenias other than the life-long microcytic anaemia related to their thalassemia trait or because their known and usual anaemic state had deteriorated without this being explainable by another secondary cause of anaemia. The nine patients had a median age of 80 years (range: 66–89 years) and six were female. Five of the nine patients were under our attention after the discovery of one or two cytopenias, other than microcytic anaemia, during a work-up for the diagnosis of MDS. The remaining four patients were well-known carriers of heterozygous α (n =1) and β (n =3) thalassaemic traits and were referred to our clinic because of worsening anaemia to the point of needing transfusion. After a comprehensive work-up, the subtypes of MDS diagnosed were refractory anaemia (RA) without sideroblasts, refractory cytopenia with multilineage dysplasia (RCMD) and refractory anaemia with excess blasts-1 (RAEB-1) in four, three and two cases, respectively. The percentages of blast cells ranged from 1% to 7%. Standard cytogenetic and fluorescence in situ hybridization analyses showed karyotypic abnormalities, such as Y chromosome loss (2 patients), 20q12 deletion (1 patient) and trisomy 8 (1 patient); five patients had no cytogenetically detectable genetic changes. According to the International Prognostic Scoring System2, seven patients had low-risk MDS, while the other two patients had intermediate-1 disease. In three cases we opted for clinical observation whereas six patients were treated with recombinant human erythropoietin.
Considering the four patients who were referred to us because of progressively worsening anaemia after other secondary causes had been ruled out and the use of standard measures of treatment had failed, three had cytopenias other than anaemia whereas the only haematological abnormality in the remaining case was an important reduction of haemoglobin level. All four patients had hypercellular bone marrow with prominent erythroid hyperplasia, indicating markedly ineffective erythropoiesis probably due to increased apoptosis, together with variable megakaryocytic and granulocytic dysplasia. Three out of these four patients had a cytogenetic abnormality (one each with loss of Y chromosome, the 20q12 deletion and trisomy 8). Three had RA whereas the other had RCMD. All four patients were administered erythropoietin, given that their endogenous erythropoietin concentrations, ranging from 48 to 114 U/L, were inappropriately low for the degree of anaemia. The dose of erythropoietin was titrated according to individual targets determined from the basic α and β thalassemia trait-induced haemoglobin concentrations and the usual red blood cell counts typically recorded in each patient. All treated patients responded to erythropoietin and achieved transfusion independence, although two of these four patients had required transfusions before (1 case) or soon after the initial phase (1 case) of the treatment.
Considering all nine patients, after a median follow-up of 19 months (range, 2–36 months), no disease progression or evolution in acute myeloid leukaemia was observed. In conclusion, α and β thalassaemia traits may be an incidental finding in cytopenic patients developing MDS; on the other hand, worsening anaemia in a subject with α- or β-thalassemia trait can be accompanied by myelodysplastic changes in the bone marrow. Certainly, cytogenetic and molecular studies are crucial to define the diagnosis and all the possible factors implicated in the pathogenesis of these low grade MDS must be investigated. Further epidemiological and clinical studies, especially among populations in whom thalassaemia mutations are relatively common, should clarify the extent of this phenomenon. In addition, different systems of prognostic stratification should be developed for these patients. In fact, we believe that the currently validated prognostic systems for MDS2,3 are not fully suitable and applicable to this category of patients, in particular when considering the haemoglobin levels. Indeed, under normal conditions, these patients have remained asymptomatic for many years regardless of their low haemoglobin levels. The current MDS classification systems may overestimate, at least in part, the weight of the haemoglobin values which have been usual in the life course of these individuals and only partially due to the ineffective erythropoiesis induced by the MDS. For patients with α and β-thalassemia traits who develop worsening anaemia until becoming symptomatic, an evolution associated with major dyserythropoietic alterations in the bone marrow, a possible increase in apoptosis should be investigated. Whether these forms of MDS are true cases of MDS or aggravating apoptotic disease in the context of a stressed and hyperproliferative erythropoiesis remains a matter of debate. In this regard, the role of several erythropoietic stress factors, including iron overload, occult inflammation, a relative deficit in erythropoietin concentration and/or the development of intrinsic mechanisms of resistance to the stimulating effects of erythropoietin, are matters of speculation and should be the subject of specifically designed future studies.
Scholars Journal of Applied Medical Sciences · 2023 · 1 citations · open access
Alpha- Thalassemia: An Overview
AbstractAlpha-Thalassemia is the commonest hereditary monogenic disease worldwide. α-thalassemia is caused by α-globin gene losses and categorized into α-thalassemia 1 and α-thalassemia 2 depending on how many α-globin genes are functioning. Α thalassemia 1 is defined by inactivation of both α-globin genes on a chromosome, while in α-thalassemia 2, one gene is active. The clinical phenotype depends on the degree of genes impairment. This review will present an overview of α-thalassemia, its incidence, causes, and clinical characterization, and discuss different laboratory techniques used for the diagnosis.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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