Browsing by Subject "HEMATOPOIESIS"

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  • Gasparini, Vanessa Rebecca; Binatti, Andrea; Coppe, Alessandro; Teramo, Antonella; Vicenzetto, Cristina; Calabretto, Giulia; Barila, Gregorio; Barizza, Annica; Giussani, Edoardo; Facco, Monica; Mustjoki, Satu; Semenzato, Gianpietro; Zambello, Renato; Bortoluzzi, Stefania (2020)
    The molecular pathogenesis of chronic lymphoproliferative disorder of natural killer (NK) cells (CLPD-NK) is poorly understood. Following the screening of 57 CLPD-NK patients, only five presented STAT3 mutations. WES profiling of 13 cases negative for STAT3/STAT5B mutations uncovered an average of 18 clonal, population rare and deleterious somatic variants per patient. The mutational landscape of CLPD-NK showed that most patients carry a heavy mutational burden, with major and subclonal deleterious mutations co-existing in the leukemic clone. Somatic mutations hit genes wired to cancer proliferation, survival, and migration pathways, in the first place Ras/MAPK, PI3K-AKT, in addition to JAK/STAT (PIK3R1 and PTK2). We confirmed variants with putative driver role of MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, and TNFRSF1A genes, and of genes linked to viral infections (DDX3X and RSF1) and DNA repair (PAXIP1). A truncating mutation of the epigenetic regulator TET2 and a variant likely abrogating PIK3R1-negative regulatory activity were validated. This study significantly furthered the view of the genes and pathways involved in CLPD-NK, indicated similarities with aggressive diseases of NK cells and detected mutated genes targetable by approved drugs, being a step forward to personalized precision medicine for CLPD-NK patients.
  • Lankelma, Jacqueline M.; Belzer, Clara; Hoogendijk, Arie J.; de Vos, Alex F.; de Vos, Willem M.; van der Poll, Tom; Wiersinga, W. Joost (2016)
    OBJECTIVES: Broad-spectrum antibiotics disrupt the intestinal microbiota. The microbiota is essential for physiological processes, such as the development of the gut immune system. Recent murine data suggest that the intestinal microbiota also modulates systemic innate immune responses; however, evidence in humans is lacking. METHODS: Twelve healthy young men were given oral broad-spectrum antibiotics (ciprofloxacin 500 mg bid, vancomycin 500 mg tid and metronidazole 500 mg tid) for 7 days. At baseline, 1 day, and 6 weeks after antibiotics, blood and feces were sampled. Whole blood and isolated mononuclear cells were stimulated with selected Toll-like receptor agonists and heat-killed bacteria. Microbiota diversity and composition was determined using bacterial 16S rDNA sequencing. RESULTS: One day after the antibiotic course, microbial diversity was significantly lower compared with baseline. After antibiotic therapy, systemic mononuclear cells produced lower levels of tumor necrosis factor (TNF)-alpha after ex vivo stimulation with lipopolysaccharide (LPS). This diminished capacity to produce TNF-alpha was restored 6 weeks after cessation of antibiotic therapy. In whole blood, a reduced capacity to release interleukin (IL)-1 beta and IL-6 was observed after LPS stimulation. Antibiotic treatment did not impact on differential leukocyte counts, phagocytosis, and cell surface markers of neutrophils and monocytes. CONCLUSIONS: In this proof-of-principle study of healthy subjects, microbiota disruption by broad-spectrum antibiotics is reversibly associated with decreased systemic cellular responsiveness towards LPS. The implications of these findings in a clinical setting remain to be determined.
  • Konttinen, Henna; Cabral-da-Silva, Mauricio e Castro; Ohtonen, Sohvi; Wojciechowski, Sara; Shakirzyanova, Anastasia; Caligola, Simone; Giugno, Rosalba; Ishchenko, Yevheniia; Hernández, Damián; Fazaludeen, Mohammad Feroze; Eamen, Shaila; Budia, Mireia Gómez; Fagerlund, Ilkka; Scoyni, Flavia; Korhonen, Paula; Huber, Nadine; Haapasalo, Annakaisa; Hewitt, Alex W.; Vickers, James; Smith, Grady C.; Oksanen, Minna; Graff, Caroline; Kanninen, Katja M.; Lehtonen, Sarka; Propson, Nicholas; Schwartz, Michael P.; Pébay, Alice; Koistinaho, Jari; Ooi, Lezanne; Malm, Tarja (2019)
    Summary Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac. The iMGLs express microglial signature genes and respond to ADP with intracellular Ca2+ release distinguishing them from macrophages. Using 16 iPSC lines from healthy donors, AD patients and isogenic controls, we reveal that the APOE4 genotype has a profound impact on several aspects of microglial functionality, whereas PSEN1ΔE9 and APPswe mutations trigger minor alterations. The APOE4 genotype impairs phagocytosis, migration, and metabolic activity of iMGLs but exacerbates their cytokine secretion. This indicates that APOE4 iMGLs are fundamentally unable to mount normal microglial functionality in AD.
  • Chattopadhyay, Subhayan; Zheng, Guoqiao; Sud, Amit; Yu, Hongyao; Sundquist, Kristina; Sundquist, Jan; Försti, Asta; Hemminki, Akseli; Houlston, Richard; Hemminki, Kari (2018)
    Background Although advances in the treatment of myeloid neoplasms have led to improved patient survival, this improvement has been accompanied by an increased risk of second primary cancer (ie, the risk of another cancer after myeloid neoplasia). We aimed to assess bi-directional associations between myeloid cancers and other cancers-ie, development of second primary cancer in patients who have previously had myeloid cancer, and risks of myeloid neoplasia in patients who have previously had another cancer-to provide insight into possible mechanisms beyond side-effects of treatment and shared risk factors. Methods Using the Swedish Family-Cancer Database, we identified 35 928 individuals with primary myeloid cancer, including myeloproliferative neoplasms, acute myeloid leukaemia, chronic myeloid leukaemia, and myelodysplastic syndrome diagnosed between 1958 and 2015. The Swedish Family-Cancer Database includes every individual registered as a resident in Sweden starting in 1932, with full parental history. The primary endpoint was the assessment of relative risks (RRs) for second primary cancer, which we performed using means of incidence rate ratios, regressed over a generalised Poisson model. Findings Between 1958 and 2015, overall relative risk of second primary cancers was significantly increased after acute myeloid leukaemia (RR 1.29, 95% CI 1.17-1.41), chronic myeloid leukaemia (1.52, 1.35-1.69), myelodysplastic syndrome (1.42, 1.26-1.59), and all myeloproliferative neoplasms (1.37, 1.30-1.43) relative to the incidence of these cancers as first primary cancer. With myeloid neoplasia as a second primary cancer, risks were significantly increased for acute myeloid leukaemia (1.57, 1.48-1.65), chronic myeloid leukaemia (1.26, 1.13-1.40), and myelodysplastic syndrome (1.54, 1.42-1.67) relative to the incidence of these myeloid neoplasms as first primary cancers. Relative risk of upper aerodigestive tract cancer, squamous cell skin cancer, and non-Hodgkin lymphoma as second primary cancers were increased after all four types of myeloid neoplasia relative to their incidence as first primary cancers. High risks of myelodysplastic syndrome and acute myeloid leukaemia as second primary cancers were found after haematological cancers (RRs between 5.08 and 10.04). Interpretation The relative risks of second primary cancer are important for the long-term management of patients with myeloid cancers. The bi-directional associations of myeloid cancers with many other cancers suggest a number of candidate mechanisms that might contribute to the development and aetiology of a second primary cancer. These mechanisms might include immune dysfunction or the effects of treatment, and these should be assessed in future investigations. Copyright (c) 2018 Elsevier Ltd. All rights reserved.
  • Savola, Paula; Martelius, Timi; Kankainen, Matti; Huuhtanen, Jani; Lundgren, Sofie; Koski, Yrjö; Eldfors, Samuli; Kelkka, Tiina; Keränen, Mikko A. I.; Ellonen, Pekka; Kovanen, Panu E.; Kytölä, Soili; Saarela, Janna; Lahdesmaki, Harri; Seppänen, Mikko R. J.; Mustjoki, Satu (2020)
    Common variable immunodeficiency (CVID) and other late-onset immunodeficiencies often co-manifest with autoimmunity and lymphoproliferation. The pathogenesis of most cases is elusive, as only a minor subset harbors known monogenic germline causes. The involvement of both B and T cells is, however, implicated. To study whether somatic mutations in CD4(+) and CD8(+) T cells associate with immunodeficiency, we recruited 17 patients and 21 healthy controls. Eight patients had late-onset CVID and nine patients other immunodeficiency and/or severe autoimmunity. In total, autoimmunity occurred in 94% and lymphoproliferation in 65%. We performed deep sequencing of 2,533 immune-associated genes from CD4(+) and CD8(+) cells. Deep T-cell receptor b-sequencing was used to characterize CD4(+) and CD8(+) T-cell receptor repertoires. The prevalence of somatic mutations was 65% in all immunodeficiency patients, 75% in CVID, and 48% in controls. Clonal hematopoiesis-associated variants in both CD4(+)and CD8(+) cells occurred in 24% of immunodeficiency patients. Results demonstrated mutations in known tumor suppressors, oncogenes, and genes that are critical for immuneand proliferative functions, such as STAT5B (2 patients), C5AR1 (2 patients), KRAS (one patient), and NOD2 (one patient). Additionally, as a marker of T-cell receptor repertoire perturbation, CVID patients harbored increased frequencies of clones with identical complementarity determining region 3 sequences despite unique nucleotide sequences when compared to controls. In conclusion, somatic mutations in genes implicated for autoimmunity and lymphoproliferation are common in CD4(+) and CD8(+) cells of patients with immunodeficiency. They may contribute to immune dysregulation in a subset of immunodeficiency patients.
  • Savola, P.; Kelkka, T.; Rajala, H. L.; Kuuliala, A.; Kuuliala, K.; Eldfors, S.; Ellonen, P.; Lagstrom, S.; Lepisto, M.; Hannunen, T.; Andersson, E. I.; Khajuria, R. K.; Jaatinen, T.; Koivuniemi, R.; Repo, H.; Saarela, J.; Porkka, K.; Leirisalo-Repo, M.; Mustjoki, S. (2017)
    Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8(+) T-cell clones; in 20% (5/25) of patients CD8(+) T cells, but not CD4(+) T cells, harbour somatic mutations. In healthy controls (n = 20), only one mutation is identified in the CD8(+) T-cell pool. Mutations exist exclusively in the expanded CD8(+) effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8(+) T cells, which may have pathogenic significance for RA and other autoimmune diseases.