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

Abstract

Bone marrow failure (BMF) syndromes are a heterogenous group of non-malignant hematologic 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.

Large Granular Lymphocytic Leukemia: From Immunopathogenesis to Treatment of Refractory Disease

“…For instance, Risankizumab is a humanized IgG1 mAB selectively inhibiting IL-23, producing complete inhibition of the IL-23 and IL-17 axis [75]. IL-23 has been found to induce IFN-γ production in T-and NK-cells, being able to activate the JAK-STAT pathway and ultimately resulting in the differentiation of TH17 cells [76][77][78]. These are specialized helper T-cells producing IL-17 and thereby influencing the NF-kβ pathway, and have been implicated in the pathogenesis of a variety of autoimmune diseases.…”

The Value of Flow Cytometry Clonality in Large Granular Lymphocyte Leukemia

“…Once activated, LGLs expand under interleukin (IL)-15 and platelet-derived growth factor (PDGF) stimulation. IL-15, a proinflammatory cytokine, is overexpressed in LGL leukemia and drives clonal transformation of normal activated cytotoxic T cells, likely through centrosome alterations, aneuploidy, and increased resistance to apoptosis [ 2 , 32 , 33 , 34 ]. In addition, IL-15 induces transcription of several anti-apoptotic proteins, such as Bcl-2, while increases proteasome-mediated degradation of pro-apoptotic factors, such as Bid, resulting in increased cell survival [ 35 ].…”

“…IL-15 also upregulates MYC , AURKA , and AURKB , responsible for centrosome alterations, and DNMT3B , ultimately leading to hypermethylation of tumor suppressor genes [ 36 , 37 ]. However, pathogenesis of LGL leukemia is not driven only by chronic antigen and proinflammatory cytokine stimulation, but also by constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway and resistance to Fas/Fas-ligand (Fas-L)-mediated apoptosis [ 1 , 2 , 38 ]. IL-6, another proinflammatory cytokine increased in the sera of LGL leukemia patients, is the main activator of STAT3, and is supposed to be mostly released by DCs [ 39 , 40 ].…”

“…LGL leukemia is considered a bone marrow failure (BMF) syndrome because of its overlapping pathogenesis with other immune-mediated diseases [ 2 ], and because LGLs can be frequently found in patients diagnosed with BMF syndromes, such as pure red cell aplasia (PRCA) and acquired aplastic anemia (AA) [ 3 ]. LGL leukemia of mature T cells is the most common entity (85% of cases), usually occurring with an indolent clinical course, while NK-LGL leukemia is rare but aggressive and frequently associated with Epstein–Barr virus (EBV) infection in young Asian adults [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. LGLs are large-sized (15–18 µm) lymphocytes with an abundant cytoplasm containing azurophilic granules, and a round or reniform nucleus with mature chromatin [ 1 ].…”

“…Large granular lymphocyte (LGL) leukemia is a chronic lymphoproliferative disorder arising from clonal expansion of mature T or Natural Killer (NK) cells, and accounts for 2-5% of all cases of non-Hodgkin lymphomas (NHL) in Western countries [1]. LGL leukemia is considered a bone marrow failure (BMF) syndrome because of its overlapping pathogenesis with other immune-mediated diseases [2], and because LGLs can be frequently found in patients diagnosed with BMF syndromes, such as pure red cell aplasia (PRCA) and acquired aplastic anemia (AA) [3]. LGL leukemia of mature T cells is the most common entity (85% of cases), usually occurring with an indolent clinical course, while NK-LGL leukemia is rare but aggressive and frequently associated with Epstein-Barr virus (EBV) infection in young Asian adults [1][2][3][4][5][6][7][8].…”