Interleukin-6 and Interleukin-1 enhancement of GM-CSF-dependent proliferation of haematopoietic progenitor cells in myelodysplastic syndromes

Schipperus, Martin R.; Sonneveld, Pieter; Lindemans, Jan; Lom, Kirsten van; Vlastuin, M.; Abels, J.

doi:10.1111/j.1365-2141.1991.tb08619.x

Cited by 13 publications

(4 citation statements)

References 29 publications

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“…15 In particular, IL-6 influences HSC development and has paracrine function in HSPC, leading to overproduction of myeloid cells and aberrant hematologic features found in MDS patients. [16][17][18] Second, our results raise the possibility that altered innate immune signaling induced by spliceosome mutations could alter immune cell function, contributing to the increased risk of infection and/or hyperinflammatory features common to MDS patients, 19,20 a possibility that we will explore in future studies. Finally, while we focus on the role of spliceosome mutations in MDS, spliceosome mutations are present in many hematologic malignancies 1 and could affect pathogenesis of other cancers using similar mechanisms.…”

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confidence: 90%

Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling

et al. 2019

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Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling Genes encoding spliceosome components including SF3B1, U2AF1, and SRSF2, are frequently somatically mutated in myelodysplastic syndromes (MDS), other hematologic malignancies, and solid tumors. 1 Typically these are mutually exclusive, heterozygous, missense, hotspot mutations that result in neomorphic or gain-offunction splicing phenotypes. These mutations alter splicing of many genes; however, overlap among the different splicing factors is limited. Thus, a common mechanism by which spliceosome mutations contribute to disease is suspected but has remained elusive. We previously demonstrated that inhibiting any of five different spliceosome genes (SF3B1, SF3A1, SF3A2, SF3A3, EFTUD2) in mouse or human macrophages reduces inflammatory cytokine production induced by multiple Toll-like receptor (TLR) agonists including the TLR4 agonist lipopolysaccharide (LPS). 2-5 Although these genes encode essential spliceosome components, partial gene knockdown (approx. 80%) reduces LPS-induced inflammatory cytokine production without affecting viability or phagocytosis. 2-5 Hence, innate immunity may be particularly sensitive to spliceosome perturbation. These observations suggest that MDS-associated spliceosome mutations might enhance innate immunity,

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confidence: 90%

Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling

et al. 2019

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“…[14, 15, 11, 7, 16–19] Similarly, IL-6 has also been implicated in aspects of the MDS phenotype, including induction of increased cell proliferation and hypoferremia due to increased hepcidin, which contributes to anemia. [20–22] Clinically, aberrant cytokine secretion patterns, specifically elevated levels of TNFα and IL-6, are also associated with reduced quality of life and inferior leukemia-free and overall survival. [23, 24, 12] Recently, pyroptosis, a novel mode of inflammatory cell death, has been elucidated in MDS.…”

Section: Introductionmentioning

confidence: 99%

Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes

Ivy

Ferrell

2018

Curr Hematol Malig Rep

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Immune alterations in MDS are complex, heterogeneous, and intertwined with clonal hematopoiesis and stromal cell dysfunction. Inflammation in MDS proceeds as a vicious cycle, mediated in large part by secreted factors, which induce cell death and activate innate immune signaling. Therapeutic targeting of this variable immune dysregulation has led to modest responses thus far, but incorporation of the growing repertoire of immunotherapy brings new potential for improved outcomes. The immune milieu is variable across the spectrum of MDS subtypes, with a changing balance of inflammatory and suppressive cellular forces from low- to high-risk disease.

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“…Despite no extrinsic agent has been implicate, there is evidence of an inflammation process in MDS BM (Figure 2 ). Numerous studies report there are high productions of TNFα, IFNγ, IL-1α; IL-6, IL-17, TGFβ, using different techniques such as immuno-histology, BM dosages, functional analyses, and even in peripheral blood dosages ( 22 – 32 ). These cytokines can be produced not only by resident macrophages and attracted lymphocytes but also by stromal cells and stem cells.…”

Section: Immune Disorders Associated With Myelodysplastic Bone Marrowmentioning

confidence: 99%

Bone Marrow Immunity and Myelodysplasia

Lambert¹,

Aanei

2016

Front. Oncol.

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Myelodysplastic syndrome (MDS) is characterized by an ineffective hematopoiesis with production of aberrant clones and a high cell apoptosis rate in bone marrow (BM). Macrophages are in charge of phagocytosis. Innate Immune cells and specific T cells are in charge of immunosurveillance. Little is known on BM cell recruitment and activity as BM aspirate is frequently contaminated with peripheral blood. But evidences suggest an active role of immune cells in protection against MDS and secondary leukemia. BM CD8+ CD28− CD57+ T cells are directly cytotoxic and have a distinct cytokine signature in MDS, producing TNF-α, IL-6, CCL3, CCL4, IL-1RA, TNFα, FAS-L, TRAIL, and so on. These tools promote apoptosis of aberrant cells. On the other hand, they also increase MDS-related cytopenia and myelofibrosis together with TGFβ. IL-32 produced by stromal cells amplifies NK cytotoxicity but also the vicious circle of TNFα production. Myeloid-derived suppressing cells (MDSC) are increased in MDS and have ambiguous role in protection/progression of the diseases. CD33 is expressed on hematopoietic stem cells on MDS and might be a potential target for biotherapy. MDS also has impact on immunity and can favor chronic inflammation and emergence of autoimmune disorders. BM is the site of hematopoiesis and thus contains a complex population of cells at different stages of differentiation from stem cells and early engaged precursors up to almost mature cells of each lineage including erythrocytes, megakaryocytes, myelo-monocytic cells (monocyte/macrophage and granulocytes), NK cells, and B cells. Monocytes and B cell finalize their maturation in peripheral tissues or lymph nodes after migration through the blood. On the other hand, T cells develop in thymus and are present in BM only as mature cells, just like other well vascularized tissues. BM precursors have a strong proliferative capacity, which is usually associated with a high risk for genetic errors, cell dysfunction, and consequent cell death. Abnormal cells are prone to destruction through spontaneous apoptosis or because of the immunosurveillance that needs to stay highly vigilant. High rates of proliferation or differentiation failures lead to a high rate of cell death and massive release of debris to be captured and destroyed (1). Numerous macrophages reside in BM in charge of home-keeping. They have a high capacity of phagocytosis required for clearing all these debris.

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Interleukin-6 and Interleukin-1 enhancement of GM-CSF-dependent proliferation of haematopoietic progenitor cells in myelodysplastic syndromes

Cited by 13 publications

References 29 publications

Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling

Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling

Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes

Bone Marrow Immunity and Myelodysplasia

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