The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis
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 recog...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/8/1249 |
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| author | Nozomu Kawashima Valentino Bezzerri Seth J. Corey |
| author_facet | Nozomu Kawashima Valentino Bezzerri Seth J. Corey |
| author_sort | Nozomu Kawashima |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T00:05:26Z |
| format | Article |
| id | doaj.art-70ab7213ba714db4b8fa3c33cfc3e5e7 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T00:05:26Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-70ab7213ba714db4b8fa3c33cfc3e5e72023-11-19T00:24:19ZengMDPI AGBiomolecules2218-273X2023-08-01138124910.3390/biom13081249The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their PathogenesisNozomu Kawashima0Valentino Bezzerri1Seth J. Corey2Departments of Pediatrics and Cancer Biology, Cleveland Clinic, Cleveland, OH 44195, USACystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, 37126 Verona, ItalyDepartments of Pediatrics and Cancer Biology, Cleveland Clinic, Cleveland, OH 44195, USAInherited 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.https://www.mdpi.com/2218-273X/13/8/1249Fanconi anemiaShwachman–Diamond syndromedyskeratosis congenitainflammatory cytokines |
| spellingShingle | Nozomu Kawashima Valentino Bezzerri Seth J. Corey The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis Biomolecules Fanconi anemia Shwachman–Diamond syndrome dyskeratosis congenita inflammatory cytokines |
| title | The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis |
| title_full | The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis |
| title_fullStr | The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis |
| title_full_unstemmed | The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis |
| title_short | The Molecular and Genetic Mechanisms of Inherited Bone Marrow Failure Syndromes: The Role of Inflammatory Cytokines in Their Pathogenesis |
| title_sort | molecular and genetic mechanisms of inherited bone marrow failure syndromes the role of inflammatory cytokines in their pathogenesis |
| topic | Fanconi anemia Shwachman–Diamond syndrome dyskeratosis congenita inflammatory cytokines |
| url | https://www.mdpi.com/2218-273X/13/8/1249 |
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