Myelo-deception: Luspatercept &amp; TGF-Beta ligand traps in myeloid diseases &amp; anemia

Feld, Jonathan; Navada, Shyamala C.

doi:10.1016/j.leukres.2020.106430

Cited by 10 publications

(7 citation statements)

References 80 publications

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“…Furthermore, some drugs, not yet in clinical trials, seem to be promising treatments. For instance, activin receptor ligand traps displayed preclinical promising efficacy in other diseases, such as Diamond-Blackfan anemia and other types of anemia [13], and Luspatercept could also be assessed in combination with other approved agents for anemia (e.g., ESAs) or with other agents targeting the TGF-β pathway (e.g., Galunisertib) to benefit from potentially synergistic or additive mechanisms of action [63,64].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Parisi

Finelli

Fazio

et al. 2021

IJMS

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Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.

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Section: Discussionmentioning

confidence: 99%

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Parisi

Finelli

Fazio

et al. 2021

IJMS

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“…Still, the contributions of inflammatory cytokines to FA pathogenesis remain to be fully determined [ 36 , 37 ]. Inhibition of TGF-β by luspatercept, a trap for the TGF family of ligands [ 38 ], may be of clinical value for the anemia of FA.…”

Section: Common Ibmfssmentioning

confidence: 99%

The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis

2023

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Inherited bone marrow failure syndromes (IBMFSs) include Fanconi anemia, Diamond–Blackfan anemia, Shwachman–Diamond syndrome, dyskeratosis congenita, severe congenital neutropenia, and other rare entities such as GATA2 deficiency and SAMD9/9L mutations. The IBMFS monogenic disorders were first recognized by their phenotype. Exome sequencing has validated their classification, with clusters of gene mutations affecting DNA damage response (Fanconi anemia), ribosome structure (Diamond–Blackfan anemia), ribosome assembly (Shwachman–Diamond syndrome), or telomere maintenance/stability (dyskeratosis congenita). The pathogenetic mechanisms of IBMFSs remain to be characterized fully, but an overarching hypothesis states that different stresses elicit TP53-dependent growth arrest and apoptosis of hematopoietic stem, progenitor, and precursor cells. Here, we review the IBMFSs and propose a role for pro-inflammatory cytokines, such as TGF-β, IL-1β, and IFN-α, in mediating the cytopenias. We suggest a pathogenic role for cytokines in the transformation to myeloid neoplasia and hypothesize a role for anti-inflammatory therapies.

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“…Except for β-thalassemia and MDS with RS, luspatercept and other activin receptor ligand traps seem to be promising treatments for Diamond–Blackfan anemia and other types of anemia [ 58 , 59 ]. Finally, luspatercept may also have synergistic or additive action when used with other pharmacological agents, such as recombinant erythropoietin, or other agents targeting the TGF-β pathway, such as Galunisertib [ 59 , 60 , 61 ].…”

Section: Other Indications and Possible Future Uses Of Luspaterceptmentioning

confidence: 99%

Luspatercept: A New Tool for the Treatment of Anemia Related to β-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis

Hatzimichael

Timotheatou²,

Koumpis

et al. 2022

Diseases

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Anemia is a common feature of both benign and malignant hematologic diseases. Beta-thalassemia (β-thalassemia) syndromes are a group of hereditary disorders characterized by ineffective erythropoiesis, due to a genetic deficiency in the synthesis of the beta chains of hemoglobin, often accompanied by severe anemia and the need for red blood cell (RBC) transfusions. Myelodysplastic syndromes (MDS) are characterized by cytopenia(s) and ineffective hematopoiesis, despite a hypercellular bone marrow. Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by reactive fibrosis of the bone marrow, accompanied by extramedullary hematopoiesis. Luspatercept, previously known as ACE-536, is a fusion protein that combines a modified activin receptor IIB (ActRIIB), a member of the transforming growth factor-β (TGF-β) superfamily, with the Fc domain of human immunoglobulin G (IgG1). It has shown efficacy in the treatment of anemia due to beta β-thalassemia, MDS and PMF and recently gained approval by the Federal Drug Agency (FDA) and the European Medicines Agency (EMA) for transfusion-dependent (TD) patients with β-thalassemia and very low to intermediate-risk patients with MDS with ringed sideroblasts who have failed to respond to, or are ineligible for, an erythropoiesis-stimulating agent. In this review, we describe the key pathways involved in normal hematopoiesis and the possible mechanism of action of luspatercept, present its development and data from the most recent clinical trials in β-thalassemia, MDS and PMF, and discuss its potential use in the treatment of these hematological disorders.

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Myelo-deception: Luspatercept & TGF-Beta ligand traps in myeloid diseases & anemia

Cited by 10 publications

References 80 publications

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis

Luspatercept: A New Tool for the Treatment of Anemia Related to β-Thalassemia, Myelodysplastic Syndromes and Primary Myelofibrosis

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