In acute leukemia, the stromal microenvironment of the bone marrow that regulates hematopoiesis is modified under the influence of malignant cells. Chemotherapy also adversely affects stromal cells. ...Multipotent mesenchymal stromal cells (MSC) are involved in the formation of the stromal microenvironment and in the regulation of normal and tumor hematopoietic cells. The properties of MSC from the bone marrow of patients with acute myeloid and lymphoid leukemia were studied at the onset of the disease and after achieving remission. The immunophenotype and the level of gene expression were analyzed in MSC of 34 patients. In MSC from patients with acute leukemia, the expression of
CD105
and
CD274
was significantly reduced in comparison with MSC from healthy donors. At the onset of the disease, the expression of
IL6
,
JAG1
,
PPARG
,
IGF1
, and
PDGFRA
was enhanced, while the expression of
IL1B
,
IL8
,
SOX9
,
ANG1,
and
TGFB
was reduced. All these changes affect the course of the disease in patients and can be the targets of therapeutic intervention.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The differentiation potential of individual clones of fibroblast CFU (CFU-F) was studied and the relative expression level of genes was analyzed in the culture of CFU-F from the bone marrow in ...patients with non-severe and severe forms of aplastic anemia at the onset of the disease. The differentiation potential of CFU-F clones was determined by the relative expression of marker genes using quantitative PCR. In aplastic anemia, the ratio of CFU-F clones with different differentiation potential changes, but the molecular mechanisms of this phenomenon are different in non-severe and severe aplastic anemia. In the culture of CFU-F in non-severe and severe aplastic anemia, the relative expression level of genes associated with the maintenance of the hematopoietic stem cell in the bone marrow niche changes, but the decrease in the expression of immunoregulatory genes occurs in severe form only, which may reflect differences in the pathogenesis of non-severe and severe aplastic anemia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In patients with acute leukemia, not only normal hematopoiesis, but also bone marrow stromal microenvironment is damaged. Multipotent mesenchymal stromal cells (MSC) are essential for the formation ...and function of the stromal microenvironment. Analysis of changes in MSC is important for the development of new approaches to leukemia therapy. The metabolism of mitochondria in MSC, relative content of mitochondrial DNA, and expression levels of genes encoding PGC-1α and Nrf2 proteins, important regulators of biogenesis, were studied using real-time PCR. Relative content of mitochondrial DNA does not change in MSC of acute leukemia patients at the onset of disease or in remission. Relative expression level of the gene encoding PGC-1α protein in MSC does not change significantly. However, relative expression level of the gene encoding Nrf2, an important antioxidant activity regulator, insignificantly decreases in patients at the onset of acute leukemia, and this decrease becomes significant upon reaching remission.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Multipotent mesenchymal stromal cells (MSC) were administered to patients after allogeneic hematopoietic stem cell transplantation to prevent the development of acute graft—versus— host disease ...(GVHD). The injection of MSC did not always prevent the development of GVHD. The aim of the work was to compare the secretome of MSC effective and ineffective in the prevention of GVHD. MSC were obtained from the bone marrow of hematopoietic stem cells donors. The secretome was studied using a TripleTOF 5600+ mass spectrometer with a NanoSpray III ion source coupled to a NanoLC Ultra 2D Plus nano-HPLC System. A total of 1,965 proteins were analyzed. Analysis of the secretome of effective and ineffective MSC samples revealed significant differences in the secretion of 1,119 proteins associated with ribosomes, exosomes, focal contacts, and others. Analysis of proteins secreted by MSC can be used to identify prognostically effective samples.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The paper describes the results of 15 consecutive Russian clinical trials in the treatment of different types of acute leukemias, conducted by Russian cooperative group within the last 27-years and ...included more than 25 hundred patients. It was shown that the 5-years overall survival in AML younger than 60 years patients improved from 20 to 33%, in ALL - from 38 to 65%, in APL - from 0 to 95%. The cooperative work resulted in balanced clinical recommendations and protocols, reproducible in regional hospitals. Though till now there is a big difference in the long term outcome in acute leukemias patients treated in coordinating or regional centers mostly due to much higher early death rate: 7.5-9.5% vs 18-25%. This parameter should be used as criteria of the total efficacy of hematological service in each region of Russia. It became possible within the last years to integrate the minimal residual disease monitoring into clinical trials thus providing a clue parameter for choosing the further therapy - allogeneic stem cell transplantation. Non - chemotherapeutic approach with arsenic trioxide and all - trans retinoid acid had dramatically changed the toxicity and duration of treatment with very high efficacy. The Russian cooperative group was the first that started to include pregnant women with acute leukemias into clinical trials. This prospective and prolonged experience has shown that pregnancy in acute myeloid leukemia is an extremely poor prognostic factor, but it does not influence the outcome in acute lymphoblastic leukemia.
Multipotent mesenchymal stromal cells (MSC) are the key regulators of hematopoiesis. We studied changes in MSC characteristics in patients with myeloid leukemia and patients with lymphoproliferative ...diseases. MSC were obtained from the bone marrow of patients at the time of diagnostic puncture using a standard technique. Their proliferative potential and expression of genes associated with differentiation and regulation of hematopoiesis were studied. The total cell production of MSC in patients with leukemia at the onset of the disease did not differ from that in the group of healthy donors. The relative expression of the
IL6
,
TGFb1
and
TGFb2
,
PPARG
genes was similar in all patients. The relative expression of the
JAG1
,
LIF
,
IGF1
,
CSF1
,
IL1b
, and
IL1bR1
genes in MSC of patients with leukemia was enhanced and the relative expression of
SDF1
was unchanged in comparison with MSC from donors. MSC from patients with leukemia were characterized by enhanced relative expression of
PDGFRA
and
PDGFRB
, and reduced expression of
SOX9
. Changes functions of the stromal microenvironment in patients with hemoblastoses attested to the role of stromal cells in the maintenance and spread of tumor cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The properties of bone marrow-derived multipotent mesenchymal stromal cells (MSC) of patients with aplastic anemia at the onset of the disease are studied insufficiently. The aim of this work was to ...test the ability of MSC from patients with aplastic anemia to maintain hematopoietic precursors and to analyze the expression of genes associated with hematopoiesis and immune response. The ability of MSC to maintain hematopoietic precursors was determined by counting cobblestone area-forming cells; gene expression was analyzed by quantitative PCR. It was shown that MSC of patients with aplastic anemia preserve their ability to maintain hematopoietic precursors. Pronounced changes in the expression of the
VEGFA
and
ANGPT1
genes were found. MSC from aplastic anemia patients with PNH clone significantly differ from those from aplastic anemia patients without PNH clone in terms of the expression of the
SDF1
,
IL1R
, and
VEGFA
genes. Changes in gene expression can be associated with the pathogenesis of the disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The present study involved three patients with graft failure following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We obtained multipotent mesenchymal stromal cells (MSCs) from ...the original hematopoietic cell donors and implanted these cells in the periosteum to treat long-term bone marrow aplasia. The results showed that in all patients endogenous blood formation was recovered 2 weeks after MSC administration. Donor MSCs were found in recipient bone marrow three and 5 months following MSC implantation. Thus, our findings indicate that functional donor MSCs can persist in patient bone marrow.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Allogeneic bone marrow transplantation (allo-BMT) is currently the only way to cure many hematoproliferative disorders. However, allo-BMT use is limited by severe complications, the foremost being ...graft-versus-host disease (GVHD). Due to the lack of efficiency of the existing methods of GVHD prophylaxis, new methods are being actively explored, including the use of donors’ multipotent mesenchymal stromal cells (MMSC). In this work, we analyzed the results of acute GVHD (aGVHD) prophylaxis by means of MMSC injections after allo-BMT in patients with hematological malignancies. The study included 77 patients. They were randomized into two groups — those receiving standard prophylaxis of aGVHD and those who were additionally infused with MMSC derived from the bone marrow of hematopoietic stem cell donors. We found that the infusion of MMSC halves the incidence of aGVHD and increases the overall survival of patients. Four of 39 MMSC samples were ineffective for preventing aGVHD. Analysis of individual donor characteristics (gender, age, body mass index) and the MMSC properties of these donors (growth parameters, level of expression of 30 genes involved in proliferation, differentiation, and immunomodulation) revealed no significant difference between the MMSC that were effective or ineffective for preventing aGVHD. We used multiple logistic regression to establish a combination of features that characterize the most suitable MMSC samples for the prevention of aGVHD. A model predicting MMSC sample success for aGVHD prophylaxis was constructed. Significant model parameters were increased relative expression of the
FGFR1
gene in combination with reduced expression levels of the
PPARG
and
IGF1
genes. Depending on the chosen margin for probability of successful application of MMSC, this model correctly predicts the outcome of the use of MMSC in 82–94% of cases. The proposed model of prospective evaluation of the effectiveness of MMSC samples will enable prevention of the development of aGVHD in the maximal number of patients.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aim. To study the risk factors, symptoms and outcomes of candidemia caused by C. albicans and C. non - albicans in patients with hematological malignancies. Materials and methods. The study included ...patients with hematological malignancies and candidemia. The diagnosis of candidemia was established according to the single isolation of Candida spp. from blood culture and the presence of symptoms of infection. Results and discussion. Over 12 years (2006-2017), candidemia was diagnosed in 75 patients aged 17 to 77 years (median 48 years). The causative agents of candidemia were C. albicans in 34.7% of patients, C. non - albicans - in 65.3%. Candidemia caused by C. albicans prevailed in patients of the older age group (median 56.5 years, p=0.04) and in patients with lymphoma (61.5%, p=0.01) with colonization of the gut by the same species of Candida (88.5%, p=0.002). Isolation of C. non - albicans from blood culture was more common in patients with acute leukemia (51%, p=0.01) and in recipients of allogeneic hematopoietic stem cells (22.5%, p=0.01). The ability to form biofilms was observed more frequently among C. non - albicans (59.2%) than C. albicans (19.2%, p=0.001). The clinical symptoms of candidemia were non - specific (fever was in 97%). Septic shock developed in 25 (33%) patients with comparable frequency in both groups. Concomitant infections was also comparable (73% vs. 73.5%). Overall 30-day survival in patients with candidemia caused by C. albicans and C. non - albicans was 61.2% and 61.5%. Treatment with echinocandin was associated with increase of survival compared to other antifungal agents among patients with C. albicans candidaemia (88.9% versus 40%, p=0.02) and among C. non - albicans (77.3% versus 47.8%). Conclusion. C. non - albicans constituted a high proportion among causative agents of candidemia. High mortality rate was observed in both groups. Initial therapy with echinocandin was associated with increase of survival.
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