scholarly journals Paraneoplastic Leukemoid Reaction Associated with Increased Levels of and Tumor Overexpression of Receptors for G-CSF, GM-CSF, and IL-6: A Clinico-Pathological-Molecular Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4945-4945 ◽  
Author(s):  
Alejandro Recio Boiles ◽  
Eric M. Lander ◽  
George S. Watts ◽  
Steffan T. Nawrocki ◽  
Andrew M. Yeager
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
Metastatic Cancer ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Fish Analysis ◽  
Leukemoid Reaction ◽  
Ifn Gamma ◽  
Gm Csf

Abstract Introduction: Paraneoplastic leukemoid reaction (PLR) comprises 10% of leukemoid reactions among patients with solid tumors, especially those with pulmonary malignancy and metastatic disease. Defined as a white blood cell (WBC) count of >50 x 109/L with mature, non-clonally derived neutrophils, and without tumor involvement in the bone marrow, PLR is associated with a poor prognosis. Systemic inflammation promotes tumor growth and metastasis; however, the mechanisms underlying PLR are not well elucidated. We performed a comprehensive clinico-pathological-molecular analysis of cytokines and gene expression in bone marrow, metastatic tumor, and serum from a 76-year-old man with metastatic poorly differentiated non-small cell lung cancer (NSCLC), hyperleukocytosis (WBC 146.5 x 109/L) and extreme neutrophilia (96% neutrophils; absolute neutrophil count 140.6 x 109/L). Methods: After informed consent, we conducted an extensive clinical evaluation of the patient's neutrophilic hyperleukocytosis. We examined the patient's peripheral blood, serum and bone marrow via histologic examination, flow cytometry, cytogenetics, and fluorescent in situ hybridization (FISH) following established protocols. We evaluated levels of 12 cytokines (G-CSF, GM-CSF, IFN-gamma, IL-1a, -2, -4, -6, -8, -10, -12, and -17a, and TNF-a) in serum by enzyme-linked immunosorbent assay (ELISA; Quantikine, R&D Systems). We compared gene expression of 30 cytokines and their receptors (CSF2/R, CSF3/R, IFN-gamma/R1, IL-1A/B/R1/RN, IL-2/RA/RB/RG, IL-4/R, IL-6/R, CXCL8/CXCR1, IL-10/RA, IL-12A/RB2, IL17/RA, and TNF-a/RSF1A/1B) on paraffin-fixed samples of the patient's NSCLC and on an age- and gender-matched sample of NSCLC from a patient without PLR (Geneticist Inc. Biorepository), using real-time polymerase chain reaction (PCR; RT2 Profiler, QIAGEN). Results: We confirmed the diagnosis of PLR after an extensive evaluation did not show any infectious or clonal myeloproliferative process. The peripheral blood smear showed marked leukocytosis, composed mainly of mature neutrophils and mild absolute monocytosis without circulating blasts or atypical cells; there was also a normochromic, normocytic anemia (hemoglobin 11.9 g/dL, hematocrit 35.7%, and MCV 94 fl) and mild thrombocytopenia (platelets 148 x 109/L). Flow cytometric analysis of peripheral blood showed granulocyte predominance (98.8% of the events) and no blast population. Bone marrow showed 40-50% cellularity, trilineage hematopoiesis, and myeloid: erythroid ratio 14.3, without dysplasia, increased blasts and metastatic cancer. FISH analysis with extended acute leukemia panel probe showed no malignancy. Cytogenetics showed 46, XY, and PCR studies were negative for mutations of JAK2 V617F and CSF3R. Serum levels of IFN-G, IL-2, IL-4, IL-10, IL-12, and IL-17a were modestly elevated relative to normal values (3.1- to 6.3-fold increase), while level of IL-1a was decreased (0.7 normal level). In contrast, the serum levels of GM-CSF (40.06 pg/mL), G-CSF (1880.63 pg/mL), and IL-6 (361.91 pg/mL) were all markedly elevated above normal by 48.2-fold, 40.1-fold, and 72.4-fold, respectively. When compared with control non-PLR NSCLC tissue, the patient's tumor showed 3-fold overexpression of the G-CSF receptor, 13.3-fold overexpression of the GM-CSF receptor, and 1.7-fold overexpression of the IL-6 receptor. However, neither PLR nor control NSCLC samples showed increased expression of genes for those cytokines (Table 1). Conclusion: In this comprehensive mechanistic analysis of PLR, we have shown that the metastatic NSCLC tumor overexpressed genes for receptors for G-CSF, GM-CSF, and IL-6, but did not overexpress the genes for those cytokines. Significantly elevated serum levels of G-CSF, GM-CSF and IL-6, synthesized from non-tumor tissues, caused hyperleukocytosis. We hypothesize that an autocrine positive feedback loop, in which these cytokines led to autostimulation of their respective aberrantly expressed receptors on tumor cells, resulted in tumor proliferation as well as off-target stimulation of granulocytopoiesis and corresponding PLR. Disclosures No relevant conflicts of interest to declare.

scholarly journals Regulation of MHC class II gene expression in macrophages by hematopoietic colony-stimulating factors (CSF). Induction by granulocyte/macrophage CSF and inhibition by CSF-1.

1989 ◽  
Vol 170 (5) ◽  
pp. 1559-1567 ◽  
Author(s):  
C L Willman ◽  
C C Stewart ◽  
V Miller ◽  
T L Yi ◽  
T B Tomasi
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Protein Expression ◽  
Mhc Class Ii ◽  
Cellular Proliferation ◽  
Ifn Gamma ◽  
Gm Csf ◽  
Ifn Alpha ◽  
Gene And Protein Expression ◽  
Alpha Beta

CSF-1 and granulocyte/monocyte CSF (GM-CSF) were shown to modulate the levels of Ia gene and protein expression in bone marrow-derived macrophages (BMM). Recombinant GM-CSF induced high levels of Ia expression, similar to the levels induced by INF-gamma, while IL-3 had no effect. In contrast, recombinant CSF-1 not only suppressed the basal levels of Ia gene and protein expression in BMM, but also inhibited the induction of Ia by IFN-gamma and GM-CSF. Basal levels of Ia were not inhibited by recombinant CSF-1 until after 16-24 h of culture, suggesting an indirect mechanism of suppression. IFN-alpha/beta and PGE2 were shown not to be involved in the CSF-1 inhibition of basal levels of Ia expression. However, the CSF-1-mediated suppression of both the basal levels of Ia expression and the induction of Ia in BMM by IFN-gamma and GM-CSF did correlate with the induction of cellular proliferation. These data imply that in addition to regulating hematopoiesis, CSFs may regulate the initiation of the immune response through their effects on Ia expression in macrophages.

Expression of BECN1 gene in Acute Myeloid Leukemia: Association with Hematological and Clinical Parameters

QJM ◽  
2021 ◽  
Vol 114 (Supplement_1) ◽  
Author(s):  
Mohamed Moustafa Ahmed ◽  
Manal Fawzy Ghozlan ◽  
Walaa Ali Mohamed ◽  
Nesma Ahmed Safwat ◽  
Noha Bassiouny Hassan
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Control Group ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Background In acute myeloid leukemia (AML), there is copy number loss in autophagic genes such as BECN1. Accordingly, decreased autophagy and the development of AML are related. BECN1 is a critical mediator that influences the onset and progress of autophagy. Objective To investigate the expression status of BECN1 gene in newly diagnosed adult AML patients and its association with various hematological parameters and clinical outcomes. Methods Case control study to study BECN1 gene expression variability between 50 newly diagnosed adult AML patients and 20 healthy age and sex matched controls, with follow up of the patients to detect its effect on induction therapy. All AML patients underwent full history taking, through clinical examination, laboratory investigations such as complete blood count (CBC) with examination of peripheral blood and bone marrow Leishman stained films, immunophenotyping, cytogenetic analysis (karyotyping/FISH analysis) and BECN1 gene expression analysis using real-time quantitative polymerase chain reaction (qRT-PCR). Results In our study, a highly significant difference was found as regards reduced expression of BECN1 gene in patients group compared to control group. We also found reduced BECN1 gene expression in both intermediate and adverse risk groups compared to favorable risk group. Reduced expression of BECN1 gene was associated with increasing age and total leukocytic count (TLC), peripheral blood (PB) and bone marrow (BM) blasts, the presence of FLT3-ITD mutation, CD34 and CD117 and in non-responders group. No statistically significant difference was found as regards haemoglobin (Hb) level, platelet (PLT) count and FAB subtypes. Conclusion Autophagy plays an important role in the pathogenesis of AML. Furthermore; the reductive regulation of the BECN1 gene may carry a poor prognosis and is associated with many well established bad prognostic factors especially FLT3-ITD mutation. Targeting autophagy pathways especially its major regulator (BECN1 gene) may become an effective and promising new line of therapy for AML patients.

IL-4 down-regulates IL-2-, IL-3-, and GM-CSF-induced cytokine gene expression in peripheral blood monocytes

1994 ◽  
Vol 68 (6) ◽  
pp. 293-298 ◽  
Author(s):  
F. H. M. Cluitmans ◽  
B. H. J. Esendam ◽  
J. E. Landegent ◽  
R. Willemze ◽  
J. H. F. Falkenburg
Keyword(s):  
Gene Expression ◽  
Peripheral Blood ◽  
Cytokine Gene Expression ◽  
Cytokine Gene ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Gm Csf

scholarly journals Anti-CD19 Chimeric Antigen Receptor T Cell Treatment of Relapsed /Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Resistant to Bruton's Tyrosine Kinase (BTK) Inhibitor

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Weihong Chen ◽  
Xin Du ◽  
Wenyujing Zhou ◽  
Changru Luo ◽  
Xiaoqing LI
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Lymph Nodes ◽  
Peripheral Blood ◽  
Serum Levels ◽  
Car T Cell ◽  
Car T ◽  
Btk Inhibitor

CASE PRESENTATION: A 68-year-old male was diagnosed with CLL/SLL in November 2007. Bone marrow asp/bx: 36.5% lymphocytes, 78% CD19, 65% ATM (11q22 deleted) positive cells, 13.5% D13S25 (13q14.3 deleted). On December 10, 2009, the patient took FCR scheme for five cycles, followed by FR scheme for one cycle, and then a month of Chlorambucil. On September 5, 2013, the patient took BR scheme for four cycles with no effect. From March 2015 to Feb 2016, 420 mg of Ibrutinib was administered daily. On January 15, 2016, the patient developed swollen lymph nodes in his right neck with intermittent lumps, fever and nausea. He was admitted into the hospital at Feb 2, 2016. Test results: multiple swollen superficial lymph nodes over the body, with the biggest measuring 60×30mm on the right neck, with no tenderness. Supplementary tests: peripheral white blood cells (WBC) 11.94×10E9/L, lymphocyte 7.5×10E9/L, CD19 cells 6.73×10E9/L, bone marrow lymphocyte 62%, peripheral blood lymphocyte 52%. Immunophenotype: CD5, CD19, CD20dim, CD23, CD11b dim, HLA-DR expression, visible CD5+CD19+ cell clusters, and visible immunoglobulin cKappa with restricted expression. On March 10, 2016, peripheral blood platelet 60 × 10E9/L, CD19 cells 1.94×10E9/L, lactate dehydrogenase 460U/L, FER 115.6ng/ml, hepatitis B virus carrier. Diagnosis: CLL/SLL IV stage, ATM (11q22) deletion, D13S25 (13q14. 3) positive, CD19 positive. Relapse of CLL/SLL occurred again after four months and at this stage the patient was considered for therapy in a clinical trial of CD19-specific chimeric antigen receptor (CAR-) T cell therapy. Ethical approval and informed consent were obtained for anti-CD19 CAR T Cell treatment of ibrutinib resistance in relapsed/refractory CLL/SLL. We infused autologous T cells transduced with a CAR T 19 retroviral vector with CLL/SLL at doses of 3.3 × 10E8 CART19 cells on Mar. 16 2016. Patients were monitored for responses, toxic effects, and the expansion and persistence of circulating CART19 cells. After CART19 cells were infused, the patient experienced chills, fever, headache, weak, anorexia, nausea, shortness of breath, chest tightness, heart palpitation, hypotension and shock for 9 days. The serum levels of IFN-Υ were at their highest at day 7 after CAR T cells infusion. Serum interleukin 6 (IL-6) was at 680pg/ml and CD3+ cells were 97.5%, CD8+ cells 72.8% (18.7-32.8%), FER was 1529.5ng/ml (Normal No. 22-322ng/ml) 14 days after CAR-T cell infusion. The serum levels of IL-6 were at their highest at day14. The patient was diagnosed as having cytokine release syndrome. After the patient took the anti-IL-6R antibody and anti-TNF antibody, he began to recover gradually. Enlarge lymph nodes shrunk after being infused with CART19 cells for 7 days. The peripheral blood CD19 B lymphocytes were 0 on day 14 after infused with CAR T19 cells. Q-PCR was used to detect the amount of the peripheral blood CART19 cells, which stood at 5485 copies/μl, 924 copies/μl, 191 copies/μl respectively 2 weeks, 6 weeks and 3 months after infusing with CART19 cells. The peripheral blood CART 19 cells were not detectable 4 months after infusing with CART19 cells until present. The lymphadenopathy was decreased gradually after 14 days of infusion. The MRI test showed that lymphadenopathy reduced markedly or disappeared after 6 months of infusion. ATM (11q22 deleted) negative, D13S25 (13q14.3 deleted) negative. After treatment with CAR T 19 cell therapy for 53 months, the patient remained disease-free, the patient's lymph nodes, lymphocytes and I mmunoglobulins were normal. CONCLUSIONS : Cancer immunotherapy as a method of cancer treatment is the most effective after conventional treatments such as radiotherapy, chemotherapy, and surgery. For BTK Inhibitor resistance in relapsed and refractory CD19+ CLL/SLL, CD19 is a favorable target, because the expression of CD19 is limited to B cells and not present in other tissues or cells. Currently, the efficacy of this treatment in treating CLL/SLL remains to be seen. The effects of chemotherapy on the patient's B cell lymphoma are negligible, due to the fact that his CLL/SLL have become relapsed and refractory. As a result we chose the CAR T19 cell therapy genetic engineering technique as a method of treatment, to which the patient has responded well. Therefor, CAR T cell technology overcome the limitations of existing cancer therapies and has great potential for development and application. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of Granulocyte-Macrophage Colony-Stimulating Factor in Acute Myeloid Leukemia/Myelodysplastic Syndromes

2018 ◽  
pp. 1-6
Author(s):  
Neemat M. Kassem ◽  
Alya M. Ayad ◽  
Noha M. El Husseiny ◽  
Doaa M. El-Demerdash ◽  
Hebatallah A. Kassem ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myeloid Leukemia ◽  
Serum Levels ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Acute Myeloid

Purpose Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine stimulates growth, differentiation, and function of myeloid progenitors. We aimed to study the role of GM-CSF gene expression, its protein, and antibodies in patients with acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) and their correlation to disease behavior and treatment outcome. The study included 50 Egyptian patients with AML/MDS in addition to 20 healthy volunteers as control subjects. Patients and Methods Assessment of GM-CSF gene expression was performed by quantitative real-time polymerase chain reaction. GM-CSF proteins and antibodies were assessed by enzyme-linked immunosorbent assay. Results There was significant decrease in GM-CSF gene expression ( P = .008), increase in serum level of GM-CSF protein ( P = .0001), and increase in anti–GM-CSF antibodies ( P = .001) in patients with AML/MDS compared with healthy control subjects. In addition, there was a significant negative correlation between serum levels of GM-CSF protein and initial peripheral blood blasts, percentage as well as response to therapy. Conclusion Any alteration in GM-CSF gene expression could have implications in leukemogenesis. In addition, GM-CSF protein serum levels could be used to predict outcome of therapy. GM-CSF antibodies may also play a role in the pathogenesis of AML/MDS. The use of these GM-CSF parameters for disease monitoring and as markers of disease activity needs further research.

Inflammatory Cytokine Gene Expression in Different Types of Granulomatous Lesions during Asymptomatic Stages of Bovine Paratuberculosis

2005 ◽  
Vol 42 (5) ◽  
pp. 579-588 ◽  
Author(s):  
S. Tanaka ◽  
M. Sato ◽  
T. Onitsuka ◽  
H. Kamata ◽  
Y. Yokomizo
Keyword(s):  
Gene Expression ◽  
Inflammatory Cytokine ◽  
Clinical Signs ◽  
Interleukin 4 ◽  
Cytokine Gene Expression ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cytokine Gene ◽  
Gm Csf ◽  
Granulomatous Lesions

The granulomatous lesions in bovine paratuberculosis have been classified into two types, i.e., the lepromatous type and the tuberculoid type. To clarify the immunopathologic mechanisms at the site of infection, we compared inflammatory cytokine gene expression between the two types of lesions. Samples were obtained from noninfected control cows ( n =5) and naturally infected cows ( n =7) that were diagnosed by enzyme-linked immunosorbent assay (ELISA) and fecal culture test. Although none of the infected cows showed clinical signs, tuberculoid lesions were observed in five cows (tuberculoid group) and lepromatous lesions in two cows (lepromatous group). Among the cytokines examined by reverse transcription-polymerase chain reaction (RT-PCR), Th2-type cytokines interleukin-4 (IL-4) and IL-10, and Th1-type cytokine IL-2 were expressed more significantly in the lepromatous group than in the tuberculoid ( P < 0.01) and noninfected groups ( P < 0.05). No statistical differences were observed in the expression of interferon-gamma, IL-1 beta, TNF-alpha, and GM-CSF among lepromatous, tuberculoid, and noninfected groups. Expression of proinflammatory cytokine IL-12 mRNA, however, did not differ among the three groups; IL-18 was expressed at lower levels in the lepromatous group than in the tuberculoid group and the noninfected group ( P < 0.0001). Moreover, the number of cells in which IL-18 mRNAs were detected by in situ hybridization was markedly decreased in the lepromatous group. These results indicate that the formation of lepromatous-type lesions or tuberculoid-type lesions may be influenced by alterations in Th1/Th2-type cytokine production and that IL-18 may play an important role in a Th1-to-Th2 switch in paratuberculosis.

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