Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis

Biavasco, Riccardo; Lettera, Emanuele; Giannetti, Kety; Gilioli, Diego; Beretta, Stefano; Conti, Anastasia; Scala, Serena; Cesana, Daniela; Gallina, Pierangela; Norelli, Margherita; Basso-Ricci, Luca; Bondanza, Attilio; Cavalli, Giulio; Ponzoni, Maurilio; Dagna, Lorenzo; Doglioni, Claudio; Aiuti, Alessandro; Merelli, Ivan; Micco, Raffaella Di; Montini, Eugenio

doi:10.1038/s41467-021-24876-1

Cited by 22 publications

(25 citation statements)

References 31 publications

(35 reference statements)

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“…p16 expression by large pale histiocytes of RDD could be considered as a senescence marker, like what has been demonstrated in ECD and LCH 35 , 36 , 43 , 44 . Activating mutations in the BRAF-MAPK pathway induces a senescence program (oncogene induced senescence, OIS), characterized by a reprogramming of mutated cells with a DNA damage response activation and a senescence-associated secretory phenotype – SASP –, affecting non-mutated bystander cells.…”

Section: Morphology Immunophenotype and Molecular Alterations In Rddsupporting

confidence: 57%

Rosai-Dorfman disease. A legacy of Professor Rosai that is still not exploited completely

Doglioni

2021

Pathologica

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Summary Rosai-Dorfman disease (RDD) is a rare form of non-Langerhans cell histiocytosis described by Rosai and Dorfman in 1969. It is a fascinating disease characterized by accumulation of large, pale histiocytes, frequently showing the emperipolesis phenomenon. The variety of pathological aspects and the spectrum of different clinical forms were deeply investigated by Prof. Rosai. Despite recent advancements in the dissection of pathogenetic mechanisms of RDD, with the identification of gene mutations in the MAP kinase pathway, several biological and clinical aspects of this disease remains to be elucidated: this is one of the Prof. Rosai’s legacies.

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Section: Morphology Immunophenotype and Molecular Alterations In Rddsupporting

confidence: 57%

Rosai-Dorfman disease. A legacy of Professor Rosai that is still not exploited completely

Doglioni

2021

Pathologica

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“…reported that mesenchymal stem/progenitor cells in middle-aged mice have an increased senescent phenotype and that NSAID treatment can improve fracture healing in middle-aged mice ( 9 ). However, emerging evidence also indicates that senescence is an upstream source of inflammatory factors ( 37 , 43 ). Biavasco et al.…”

Section: Discussionmentioning

confidence: 99%

“…Biavasco et al. reported that oncogene-activated senescence of human hematopoietic stem and progenitor cells promotes systemic inflammation by secreting TNFα ( 37 , 43 ). In the present study, we observed that treatment of CaMPCs with SC CM only induced their inflammatory phenotype, but not cellular senescence ( Supplemental Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular signatures distinguish senescent cells from inflammatory cells in aged mouse callus stromal cells

Liu

Lin²,

McDavid³

et al. 2023

Front. Endocrinol.

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Cellular senescence plays important roles in age-related diseases, including musculoskeletal disorders. Senescent cells (SCs) exert a senescence-associated secretory phenotype (SASP) by producing SASP factors, some of which overlap with factors produced by inflammatory cells (Inf-Cs). However, the differences between SCs and Inf-Cs and how they interact with each other during fracture repair have not been well studied. Here, we analyzed single cell RNA sequencing data of aged mouse fracture callus stromal cells. We defined Inf-Cs as cells that express NF-κB Rela/Relb, SCs as cells that express the senescence genes, Cdkn1a, Cdkn2a or Cdkn2c, and inflammatory SCs (Inf-SCs) as cells that express both NF-κB and senescence genes. Differentially expressed genes and pathway analyses revealed that Inf-SCs and SCs had a similar gene expression profile and upregulated pathways that are related to DNA damage/oxidation-reduction and cellular senescence, while Inf-Cs expressed different gene signatures and pathways from SCs and Inf-SCs, mainly related to inflammation. Cellchat software analysis indicated that SCs and Inf-SCs are potential ligand-producing cells that affect Inf-Cs as target cells. Cell culture experiments demonstrated that SC conditioned medium promoted inflammatory gene expression by callus-derived mesenchymal progenitor cells, and Inf-Cs had reduced osteoblast differentiation capacity. In summary, we have identified three cell subclusters associated with inflammation and senescence in callus stromal cells, predicted potential effects of Inf-SCs and SCs on Inf-Cs by production of active ligands, and demonstrated that when mesenchymal progenitors acquire inflammatory phenotypes their osteogenic potential is reduced.

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“…Molteni, R. and his colleagues found that BRAF V600E in macrophages induce hallmark immunometabolic features of trained immunity, causing activation of the AKT/mTOR signaling axis, increased glycolysis, epigenetic changes on promoters of genes encoding cytokines, and enhanced cytokine production leading to hyper-inflammatory responses [ 14 ]. Biavasco, R. and his colleagues discovered that the activation of BRAF V600E impairs HSPC function, features myeloid restricted hematopoiesis, and leads to a widespread inflammatory condition [ 15 ]. These findings reveal the cause of high inflammatory condition in ECD patient, explain the rationale for pancreatic involvement and the robust response to IFN in our case.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic involvement in Erdheim-Chester disease: a case report and review of the literature

Dai

Duan

et al. 2022

BMC Gastroenterol

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Background Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by infiltration of lipid-laden foamy macrophages within different tissues. Clinical manifestations of ECD are highly heterogeneous. Bone lesions are found in 80%-95% of patients, while extraosseous lesions usually involve the cardiovascular system, retroperitoneum, central nervous system (CNS), and skin. Pancreatic involvement in ECD has barely been reported. Case presentation A 29-year-old female initially presented with menoxenia, diabetes insipidus and diabetes mellitus. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) revealed hypermetabolic foci in the bilateral frontal lobe, saddle area, and pancreas. A 99mTc-MDP bone scrintigraphy scan revealed symmetrical increased uptake in distal femoral and proximal tibial metaphysis, which was confirmed to be osteosclerosis by high-resolution peripheral quantitative computed tomography. The patient underwent incomplete resection of the sellar mass. Histological examination of biopsies showed histiocytic aggregates, which were positive for S100 and negative for CD1a and CD207 on immunohistochemistry. Enhanced abdominal CT scan showed hypointense nodules within the body and tail of the pancreas. Endoscopic ultrasonography guided fine-needle aspiration (EUS-FNA) found no evidence of malignancy. She was diagnosed with ECD and treated with high-dose IFN-α. Repeated examinations at three-and eight-months post treatment revealed markedly reduction of both intracranial and pancreatic lesions. Conclusions ECD is a rare histiocytic neoplasm that can involve almost every organ, whereas pancreatic involvement has barely been reported to date. Here, we present the rare case of pancreatic lesions in ECD that responded well to interferon-α. We further reviewed reports of pancreatic involvement in histiocytic disorders and concluded the characteristics of such lesions to help diagnosis and treatment, in which these lesions mimicked pancreatic adenocarcinoma and caused unnecessary invasive surgeries.

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Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis

Cited by 22 publications

References 31 publications

Rosai-Dorfman disease. A legacy of Professor Rosai that is still not exploited completely

Rosai-Dorfman disease. A legacy of Professor Rosai that is still not exploited completely

Molecular signatures distinguish senescent cells from inflammatory cells in aged mouse callus stromal cells

Pancreatic involvement in Erdheim-Chester disease: a case report and review of the literature

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