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Bone Marrow Failure Syndromes, Overlapping Diseases with a Common Cytokine Signature

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International Journal of Molecular Sciences Review Bone Marrow Failure Syndromes, Overlapping Diseases with a Common Cytokine Signature Valentina Giudice 1,2,3 , Chiara Cardamone 1,4 , Massimo Triggiani 1,4,* and Carmine Selleri 1,3 1 Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, Italy; [email protected] (V.G.); [email protected] (C.C.); [email protected] (C.S.) 2 Clinical Pharmacology, University Hospital “San Giovanni di Dio e Ruggi D’Aragona”, 84131 Salerno, Italy 3 Hematology and Transplant Center, University Hospital “San Giovanni di Dio e Ruggi D’Aragona”, 84131 Salerno, Italy 4 Internal Medicine and Clinical Immunology, University Hospital “San Giovanni di Dio e Ruggi D’Aragona”, 84131 Salerno, Italy * Correspondence: [email protected]; Tel.: +39-089-672810 Abstract: Bone marrow failure (BMF) syndromes are a heterogenous group of non-malignant hemato- logic diseases characterized by single- or multi-lineage cytopenia(s) with either inherited or acquired pathogenesis. Aberrant T or B cells or innate immune responses are variously involved in the pathophysiology of BMF, and hematological improvement after standard immunosuppressive or anti-complement therapies is the main indirect evidence of the central role of the immune system in BMF development. As part of this immune derangement, pro-inflammatory cytokines play an important role in shaping the immune responses and in sustaining inflammation during marrow failure. In this review, we summarize current knowledge of cytokine signatures in BMF syndromes. Keywords: cytokines; bone marrow failure syndromes; aplastic anemia; myelodysplastic syndromes Citation: Giudice, V.; Cardamone, C.; Triggiani, M.; Selleri, C. Bone Marrow 1. Introduction Failure Syndromes, Overlapping Bone marrow failure (BMF) syndromes are a heterogeneous group of non-malignant Diseases with a Common Cytokine constitutional and acquired hematological diseases characterized by uni- or multi-lineage Signature. Int. J. Mol. Sci. 2021, 22, marrow and or peripheral blood cytopenia(s), regardless the presence of any other disorder 705. https://doi.org/10.3390/ that may affect marrow function [1–4]. BMF in constitutional syndromes is caused by inher- ijms22020705 ited germline mutations occurring in the hematopoietic stem cell (HSC) compartment or in other hematopoietic stem and progenitor cells (HSPCs), resulting in specific diseases such Received: 24 November 2020 as Fanconi anemia (FA), dyskeratosis congenita (DKC), Shwachman–Diamond syndrome Accepted: 9 January 2021 (SDS), congenital amegakaryocytic thrombocytopenia, and neutropenia (Kostman Disease), Published: 12 January 2021 as well as familial telomerase diseases. Conversely, acquired BMF syndromes result from extrinsic direct and indirect damages on the HSC pool due to chemical agents, drugs, and Publisher’s Note: MDPI stays neu- different viruses (Figure1)[ 1]. However, the indirect injury of HSC is primarily supported tral with regard to jurisdictional clai- by immune effector mechanisms, which may also be triggered by viruses or by drug ms in published maps and institutio- nal affiliations. metabolites. Regardless the type of initial injury on the bone marrow (BM), constitutional and acquired BMF syndromes share qualitative and/or quantitative disfunctions of HSCs or their progenies, which affect their self-renewal ability [2–4]. Self-renewal is a hallmark of stemness that allows long-term maintenance of a complex process called hematopoiesis, Copyright: © 2021 by the authors. Li- leading to differentiation and maturation of mature circulating cells. Hematopoiesis is censee MDPI, Basel, Switzerland. regulated by a complex network between hematopoietic and stromal cells, as well as This article is an open access article several soluble and membrane-bound cytokines within and outside the hematopoietic distributed under the terms and con- niches [1–5]. Derangement in interaction and cooperativity between cellular and cytokine ditions of the Creative Commons At- activities has been widely reported in different acquired BMF syndromes, such as acquired tribution (CC BY) license (https:// aplastic anemia (AA), hypoplastic myelodysplastic syndromes (hMDS), and chronic T and creativecommons.org/licenses/by/ natural killer (NK) granular lymphocyte disorders. 4.0/). Int. J. Mol. Sci. 2021, 22, 705. https://doi.org/10.3390/ijms22020705 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 19 different acquired BMF syndromes, such as acquired aplastic anemia (AA), hypoplastic Int. J. Mol. Sci. 2021, 22, 705 myelodysplastic syndromes (hMDS), and chronic T and natural killer (NK) granular2 of 19 lymphocyte disorders. Figure 1. Figure 1.Bone Bone marrow marrow failure failure (BMF) (BMF) syndromes’ syndromes’ pathophysiology. pathophysiology. BMF BMF syndromes syndromes are are characterized characterized by by empty empty bone bone marrowmarrow and and peripheral peripheral blood blood cytopenia(s), cytopenia(s), and and can can be be divided divided in in congenital congenital disorders, disorders, iatrogenic iatrogenic aplastic aplastic anemia anemia (AA), (AA), andand immune-mediated immune-mediated BMF. BMF. In In congenital congenital disorders, disorders, such such as as Shwachman–Diamond Shwachman–Diamond syndrome syndrome (SDS) (SDS) or or Fanconi Fanconi anemia, anemia, hematopoietichematopoietic stem stem cells cells (HSCs) (HSCs) harbor harbor mutations mutations in in genes genes important important for for normal normal hemopoiesis, hemopoiesis, which which becomes becomes insufficient insufficient overover time time in in maintaining maintaining normal normal ranges ranges of of circulating circulating cells. cells. In In iatrogenic iatrogenic AA, AA, HSCs HSCs are are directly directly damaged damaged by by external external stressors,stressors, such such as as chemicals chemicals and and radiation. radiation. In In immune-mediated immune-mediated BMF, BMF, dysregulated dysregulated immune immune responses responses can can cause cause an an autologousautologous immune immune attack attack of of cytotoxic cytotoxic T T lymphocytes lymphocytes (CTLs) (CTLs) against against HSCs HSCs or or can can suppress suppress hemopoiesis hemopoiesis through through changes changes in BM microenvironment. Clinical presentation of BMF syndromes differs among diseases; however, immunosuppressive in BM microenvironment. Clinical presentation of BMF syndromes differs among diseases; however, immunosuppressive therapies (ISTs) can often restore bone marrow cellularity, which is one of the major pieces of evidence for the immune- therapies (ISTs) can often restore bone marrow cellularity, which is one of the major pieces of evidence for the immune- mediated pathogenesis in BMF. Abbreviations. PNH, paroxysmal nocturnal hemoglobinuria; LGL, T-large granular mediatedlymphocyte pathogenesis leukemia; AA, in BMF. acquired Abbreviations. aplastic anemia; PNH, MDS, paroxysmal myelodysplastic nocturnal syndromes; hemoglobinuria; AML, acute LGL, myeloid T-large leukemia. granular lymphocyte leukemia; AA, acquired aplastic anemia; MDS, myelodysplastic syndromes; AML, acute myeloid leukemia. In this review, we provide an update of the main cytokine abnormalities involved in In this review, we provide an update of the main cytokine abnormalities involved key relevant pathways of acquired BMF syndromes sharing similar immune-mediated in key relevant pathways of acquired BMF syndromes sharing similar immune-mediated pathogenic mechanisms. pathogenic mechanisms. 2.2. Acquired Acquired Aplastic Aplastic Anemia Anemia AAAA is is a a usually usually sporadic sporadic and and immune-mediated immune-mediated BMF BMF syndrome, syndrome, likely likely caused caused by by an an autologousautologous immune immune attack attack against against HSPCs, HSPCs, and and hematological hematological recovery recovery of of blood blood counts counts afterafter immunosuppressive immunosuppressive therapies therapies (ISTs) (ISTs) is is one one of of the the strongest strongest pieces pieces of of evidence evidence for for the the immune-mediatedimmune-mediated pathogenesis pathogenesis [ 2[2].]. CytotoxicCytotoxic TT cellscells (CTLs)(CTLs) playplay aa pivotal pivotal role role in in BM BM destruction,destruction, and and type type I I interferons interferons (IFNs) (IFNs) polarize polarize the the immune immune system system toward toward T T helper helper (Th)1(Th)1 responses responses [ 2[2,6–8];,6–8]; however, however, other other T T cell cell subsets subsets and and cytokines cytokines are are involved involved in in AA AA pathogenesispathogenesis [2[2].]. OligoclonalOligoclonal expansionexpansion ofof CD8 CD8+CD28+CD28−− TT cellscells andand effectoreffector memory memory CD8CD8++CD28CD28−−CD57CD57++ TT lymphocytes lymphocytes is is frequent in AAAA andand suggestssuggests ananantigen antigen driven driven mechanismmechanism of of T-cell T-cell activation activation [9 [9–11].–11]. Immunodominant Immunodominant clones clones can can be be highly highly enriched enriched in in effectoreffector memory memory CD8 CD8++CD28−CD57CD57+ +T Tcells, cells, and and related related CDR3 CDR3 sequences sequences are are private private to AA, to AA, while they are shared between disease and healthy subjects, suggesting the existence of common epitopes [9]. T regulatory cells (Tregs) are also decreased in AA and their ability to suppress autoreactive clones is reduced, while Th17 cells, associated
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