scholarly journals Effect of A20 on glucose dependent cell migration in acute lymphoblastic leukemia

2021 ◽  
Vol 19 (2) ◽  
pp. 229-236
Author(s):  
Nguyen Thi Xuân ◽  
Dang Thanh Chung ◽  
Can Van Mao
Keyword(s):  
Cell Migration ◽  
Acute Lymphoblastic Leukemia ◽  
High Glucose ◽  
Mononuclear Cells ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Nuclear Factor Κb ◽  
Lymphoid Cells ◽  
Peripheral Blood Mononuclear ◽  
Migration Assay

Acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic malignancy characterized by aberrant proliferation of immature lymphoid cells. A20 is a deubiquitinase gene that inhibits functional activation of immune cells mediated through nuclear factor κB (NFκB)/signal transducers and activators of transcription (STAT) pathways. A20 is frequently inactivated in leukemia/lymphoma. Little is known about the involvement between A20 and STAT signalling in regulating the function of ALL blasts. The present study, therefore, explored whether migration and apoptosis of peripheral blood mononuclear cells (PBMCs) and ALL blasts in high glucose conditions is regulated by A20. To this end, ALL blasts from blood samples of fifteen patients and PBMCs from healthy individuals in the absence of A20 were examined. Gene expression profile was determined by quantitative RT-PCR, cell apoptosis by flow cytometry, and cell migration by a transwell migration assay. As a result, the expression of A20 was inactivated in ALL blasts. Cell migration, but not apoptosis of ALL-blasts was enhanced when the cells were exposed to high glucose and dependent on A20 expression, the effects were abolished by using Nifuroxazide, a STAT inhibitor. In conclusion, A20 inhibited glucose-induced migration of ALL blasts through the STAT pathway. The effect might contribute to poorer survival of ALL patients, who develop hyperglycemia during therapy.

Targeting Kinase-activating Genetic Lesions to Improve Therapy of Pediatric Acute Lymphoblastic Leukemia

2018 ◽  
Vol 25 (24) ◽  
pp. 2811-2825 ◽  
Author(s):  
Raffaella Franca ◽  
Natasa K. Kuzelicki ◽  
Claudio Sorio ◽  
Eleonora Toffoletti ◽  
Oksana Montecchini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Point Of View ◽  
Lymphoid Cells ◽  
Gene Encoding ◽  
Pediatric All ◽  
Blast Cells ◽  
Tk Inhibitors

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, characterized by an abnormal proliferation of immature lymphoid cells. Thanks to risk-adapted combination chemotherapy treatments currently used, survival at 5 years has reached 90%. ALL is a heterogeneous disease from a genetic point of view: patients’ lymphoblasts may harbor in fact several chromosomal alterations, some of which have prognostic and therapeutic value. Of particular importance is the translocation t(9;22)(q34;q11.2) that leads to the formation of the BCR-ABL1 fusion gene, encoding a constitutively active chimeric tyrosine kinase (TK): BCR-ABL1 that is present in ~3% of pediatric ALL patients with B-immunophenotype and is associated with a poor outcome. This type of ALL is potentially treatable with specific TK inhibitors, such as imatinib. Recent studies have demonstrated the existence of a subset of BCR-ABL1 like leukemias (~10-15% of Bimmunophenotype ALL), whose blast cells have a gene expression profile similar to that of BCR-ABL1 despite the absence of t(9;22)(q34;q11.2). The precise pathogenesis of BCR-ABL1 like ALL is still to be defined, but they are mainly characterized by the activation of constitutive signal transduction pathways due to chimeric TKs different from BCR-ABL1. BCR-ABL1 like ALL patients represent a group with unfavorable outcome and are not identified by current risk criteria. In this review, we will discuss the design of targeted therapy for patients with BCR-ABL1 like ALL, which could consider TK inhibitors, and discuss innovative approaches suitable to identify the presence of patient’s specific chimeric TK fusion genes, such as targeted locus amplification or proteomic biosensors.

scholarly journals Long-term stable hematopoietic chimerism following marrow transplantation for acute lymphoblastic leukemia: a case report with in vitro marrow culture studies

Blood ◽  
1983 ◽  
Vol 62 (4) ◽  
pp. 869-872 ◽  
Author(s):  
JW Singer ◽  
A Keating ◽  
R Ramberg ◽  
R McGuffin ◽  
JE Sanders ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Host Cells ◽  
Marrow Graft ◽  
Peripheral Blood Mononuclear ◽  
Hematopoietic Chimerism

Abstract This article describes the course of a patient who received an allogeneic marrow graft from his HLA-identical sister for acute lymphoblastic leukemia in second remission. In the second month after grafting, marrow aspirates showed the presence of 7%-10% lymphoblasts. In addition, cytogenetic examination indicated the persistence of host cells. Thereafter, the patient had morphologically normal marrow examinations, with no evidence for recurrent leukemia. In addition, stable hematopoietic chimerism in both the lymphoid and myeloid cell lines has persisted for over 5 yr. Between 20% and 50% of phytohemagglutinin-stimulated peripheral blood mononuclear cells were host-derived on repeated studies. A marrow sample 4 yr after transplantation was established in long-term culture and produced 2% host granulocyte-macrophage colonies at its inception, but 24% host colonies by week 4. Despite this persistent chimerism, no in vitro or in vivo abnormalities of hematopoiesis have been detected.

scholarly journals Increased lysis of patient CD10-positive leukemic cells by T cells coated with anti-CD3 Fab' antibody cross-linked to anti-CD10 Fab' antibody

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 1044-1049 ◽  
Author(s):  
K Oshimi ◽  
T Seto ◽  
Y Oshimi ◽  
M Masuda ◽  
K Okumura ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Cytotoxic T Lymphocytes ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Leukemic Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Abstract An anti-CD3 Fab' x anti-CD10 Fab' bispecific hybrid F(ab')2 antibody (Ab) was generated. This bispecific Ab had a molecular mass of 100 to 110 Kd, and the capacity to react with both CD3+ T cells and CD10+ acute lymphoblastic leukemia (ALL) cells. We studied whether cytotoxic T lymphocytes (CTLs) could lyse patient CD10+ ALL cells after addition of the bispecific Ab. As effector CTLs, interleukin-2 (IL-2)-stimulated peripheral blood mononuclear cells (PBMCs) and CTL clones were used. When IL-2-stimulated PBMCs were assayed for cytotoxicity to 61Cr- labeled CD10+ ALL cells, their activity was shown to be markedly enhanced by the addition of the bispecific Ab. Most of the CTL clones established lacked cytotoxicity for CD10+ ALL cells, but addition of the bispecific Ab induced a significant level of cytotoxicity. CTLs derived from ALL patients also showed significant cytotoxicity for autologous CD10+ ALL cells after addition of the bispecific Ab. However, this Ab did not affect the cytotoxicity of CTLs when CD10- leukemic cells were used as the targets. These findings suggest that the bispecific Ab can be used for immunotherapy in patients with CD10+ ALL.

scholarly journals Low expression of Toll-like receptors in peripheral blood mononuclear cells of pediatric patients with acute lymphoblastic leukemia

2016 ◽  
Vol 49 (2) ◽  
pp. 675-681 ◽  
Author(s):  
María Sánchez-Cuaxospa ◽  
Alejandra Contreras-Ramos ◽  
Erandi Pérez-Figueroa ◽  
Aurora Medina-Sansón ◽  
Elva Jiménez-Hernández ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Pediatric Patients ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Toll Like Receptors ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Low Expression

scholarly journals The regulatory role of peripheral blood mononuclear cell function by A20

2020 ◽  
Vol 17 (4) ◽  
pp. 603-609
Author(s):  
Nguyen Thi Xuan ◽  
Nguyen Huy Hoang
Keyword(s):  
Cell Migration ◽  
Peripheral Blood ◽  
Cell Apoptosis ◽  
Mononuclear Cells ◽  
Cell Function ◽  
Binding Capacity ◽  
Negative Regulator ◽  
Peripheral Blood Mononuclear ◽  
Migration Assay

Peripheral blood mononuclear cells (PBMC) consist of lymphocytes (T cells, B cells, natural killer cells), monocytes and dendritic cells and play important roles in initiating and regulating immunity against pathogens or immunotolerance to allergens. Activation of PBMCs is induced upon exposure to multiple stimuli by the binding with toll-like receptors (TLRs), recognition elements of the innate immune system. A20 is a negative regulator of nuclear factor (NF)-κB-dependent immune reaction in response to TLR ligands. A20-deficient mice display severe inflammation, tissue damage in multiple organs, cachexia and premature mortality. Single nucleotide polymorphisms (SNPs) at A20 gene region in humans reduce the binding capacity of A20 to NF‐κB subunits, resulting in reduced expression and function of A20 and leading to the pathogenesis of autoimmune and cancers. Although the inhibitory role of A20 on immune cells including B, T and DC functions has been previously reported, the effect of A20 on PBMC function is not mentioned yet. The present study, therefore, explored whether A20 expression is involved in immunophenotypic changes, the release of cytokine production, cell migration, and apoptosis. To this end, immonophenotypic profile and cell apoptosis were examined by flow cytometry, secretion of inflammatory cytokines by ELISA and cell migration by a transwell migration assay. As a result, percentages of CD3+CD25+, CD19+CD25+, and CD11b+CD40+ expressing cells, the release of TNF-α and IL-1β and cell migration were enhanced in A20-silenced PBMCs. However, cell apoptosis was independent of the presence of A20 in PBMCs. In conclusion, these results attained in this study suggested that A20 expression might modulate the immune response in autoimmune disease and cancers.

Co-expression of 9-O-acetylated sialoglycoproteins and their binding proteins on lymphoblasts of childhood acute lymphoblastic leukemia: an anti-apoptotic role

2009 ◽  
Vol 390 (4) ◽  
Author(s):  
Kankana Mukherjee ◽  
Anil K. Chava ◽  
Suman Bandyopadhyay ◽  
Asish Mallick ◽  
Sarmila Chandra ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Binding Proteins ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Serum Starvation ◽  
Peripheral Blood Mononuclear ◽  
Childhood All

AbstractEnhanced levels of 9-O-acetylated sialoglycoproteins (Neu5,9Ac2GPs) as disease-associated molecules was reported to act as signaling molecules for promoting survival of lymphoblasts in childhood acute lymphoblastic leukemia (ALL). Here, we searched for potential physiological ligands for Neu5,9Ac2GPs that could be involved in modulating the survival of lymphoblasts. Accordingly, we examined the presence of binding proteins for Neu5,9Ac2GPs on cell lines and primary cells of patients with B- and T-ALL, at presentation of the disease. Peripheral blood mononuclear cells from normal healthy donors and cells from myeloid leukemia patients were used for comparison. Neu5,9Ac2GPs-binding proteins (BPs) were specifically detected on the surface of both T- and B-ALL-lymphoblasts and ALL-cell lines along with the consistent presence of Neu5,9Ac2GPs. The Neu5,9Ac2GPs and BPs also co-localized on the cell surface and interacted specificallyin vitro. Apoptosis of lymphoblasts, induced by serum starvation, was reversed in the presence of purified Neu5,9Ac2GPs due to possible engagement of BPs, and the anti-apoptotic role of this interaction was established. This is the first report of the presence of potential physiological ligands for disease-associated molecules like Neu5,9Ac2GPs, the interaction of which is able to trigger an anti-apoptotic signal conferring a survival advantage to leukemic cells in childhood ALL.

scholarly journals Identification of Differentially Expressed Genes Associated with Prognosis of B Acute Lymphoblastic Leukemia

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Idalia Garza-Veloz ◽  
Margarita L. Martinez-Fierro ◽  
Jose Carlos Jaime-Perez ◽  
Karol Carrillo-Sanchez ◽  
Maria Guadalupe Ramos-Del Hoyo ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Type B ◽  
Peripheral Blood Mononuclear ◽  
Independent Prognostic Significance ◽  
Study Population ◽  
Polymerase Chain ◽  
The Times

Background.Acute lymphoblastic leukemia type B (B-ALL) is a neoplastic disorder with high mortality rates. The aim of this study was to validate the expression profile of 45 genes associated with signaling pathways involved in leukemia and to evaluate their association with the prognosis of B-ALL.Methods.219 samples of peripheral blood mononuclear cells obtained from 73 B-ALL patients were studied at diagnosis, four, and eight weeks after starting treatment. Gene expression was analyzed by quantitative real-time polymerase chain reaction.Results.Normalized delta Cq values of 23 genes showed differences between B-ALL and controls at diagnosis time (Pvalues < 0.05). There were significant associations between B-ALL patients relapse/death and the expression levels of IL2RA, SORT1, DEFA1, and FLT3 genes at least in one of the times evaluated (Pvalues < 0.05 and odds ratio ranges: 3.73–27). The association between FLT3 deregulation and relapse/death was a constant in the times studied and their overexpression significantly increased the odds of relapse/death in a range of 3.73 and 6.05 among study population (Pvalues < 0.05).Conclusions.Overexpression of FLT3 and DEFA1 genes retained independent prognostic significance for B-ALL outcome, reflected as increased risks of relapse/death among the study population.

scholarly journals Long-term stable hematopoietic chimerism following marrow transplantation for acute lymphoblastic leukemia: a case report with in vitro marrow culture studies

Blood ◽  
1983 ◽  
Vol 62 (4) ◽  
pp. 869-872
Author(s):  
JW Singer ◽  
A Keating ◽  
R Ramberg ◽  
R McGuffin ◽  
JE Sanders ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Host Cells ◽  
Marrow Graft ◽  
Peripheral Blood Mononuclear ◽  
Hematopoietic Chimerism

This article describes the course of a patient who received an allogeneic marrow graft from his HLA-identical sister for acute lymphoblastic leukemia in second remission. In the second month after grafting, marrow aspirates showed the presence of 7%-10% lymphoblasts. In addition, cytogenetic examination indicated the persistence of host cells. Thereafter, the patient had morphologically normal marrow examinations, with no evidence for recurrent leukemia. In addition, stable hematopoietic chimerism in both the lymphoid and myeloid cell lines has persisted for over 5 yr. Between 20% and 50% of phytohemagglutinin-stimulated peripheral blood mononuclear cells were host-derived on repeated studies. A marrow sample 4 yr after transplantation was established in long-term culture and produced 2% host granulocyte-macrophage colonies at its inception, but 24% host colonies by week 4. Despite this persistent chimerism, no in vitro or in vivo abnormalities of hematopoiesis have been detected.

scholarly journals Purine nucleoside phosphorylase activity in acute lymphoblastic leukemia

Blood ◽  
1980 ◽  
Vol 56 (3) ◽  
pp. 380-382
Author(s):  
J Blatt ◽  
GH Reaman ◽  
N Levin ◽  
DG Poplack
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Purine Nucleoside Phosphorylase ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Peripheral Blood Mononuclear ◽  
Normal Peripheral Blood ◽  
Blood Mononuclear Cells

Purine nucleoside phosphorylase (PNP) activity has been measured in the lymphoblasts of 22 patients with acute lymphoblastic leukemia (ALL) and correlated with routine immunologic cell surface markers. Fourteen of the 22 patients were considered to have non-T, non-B-cell ALL; 8 patients had T-cell disease. The median PNP activity in 21 control samples of normal peripheral blood mononuclear cells was 83 U. The median PNP activity of the non-T, non-B lymphoblasts was 79 U. No statistical difference in PNP activity between these two groups could be discerned (p < 0.37). In contrast, T-cell lymphoblasts demonstrated diminished PNP activity with a median of 38 U. The differences in activity between T lymphoblasts and both non-T, non-B leukemic cells and normal peripheral blood mononuclear cells were significant (p < 0.001 and p < 0.003, respectively). Evaluation of PNP activity provides further evidence of biochemical heterogeneity among immunologic subclasses of ALL.

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