Dynamic Changes in the Ability to Release Neutrophil ExtraCellular Traps in the Course of Childhood Acute Leukemias
Magdalena OstafinOlga CiepielaMichał P. PruchniakMałgorzata WachowskaEdyta UlińskaPiotr MrówkaEliza Głodkowska-MrówkaUrszula Demkow
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Abstract:
Acute leukemias, the most common cancers in children, are characterized by excessive proliferation of malignant progenitor cells. As a consequence of impaired blood cell production, leukemia patients are susceptible to infectious complications—a major cause of non-relapse mortality. Neutrophil extracellular traps (NETs) are involved in various pathologies, from autoimmunity to cancer. Although aberrant NETs formation may be partially responsible for immune defects observed in acute leukemia, still little is known on the NET release in the course of leukemia. Here, we present the first comprehensive evaluation of NETs formation by neutrophils isolated from children with acute leukemia in different stages of the disease and treatment stimulated in vitro with phorbol 12-myristate 13-acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (fMLP), and calcium ionophore (CI). NETs release was measured using quantitative fluorescent method and visualized microscopically. In this setting, NETs release was significantly impaired in leukemic children both at the diagnosis and during the treatment, and full restoration of neutrophil function was achieved only after successful completion of the leukemia treatment. We suggest that neutrophil function impairment may result from both disease- and treatment-related factors. In this context, deficient innate immune response observed in acute leukemia patients may be present regardless of neutrophil count and contribute to secondary immunodeficiency observed in this population.Keywords:
Neutrophil Extracellular Traps
Pathogenesis of atypical leukemia (hypoplastic leukemia and smoldering acute leukemia) is still unknown. The author intended to find the factors inducing its unique clinical course by comparing 5 cases of atypical leukemia with the same numder of typical acute leukemia with respect to their blasts cell size, laveling index with (3)H-thymidine and pattern of tissue growth by the bone marrow culture method devised by us. And obtained the following results. 1) The size of 100 blasts chosen randomely out of the bone marrow smear prepared from 5 cases of atypical leukemia was compared with those of typical acute leukemia. The mean val-ue of the former group was 41.9±12.3, while that of the latter was 61.4±16.7. There fore, the size of blasts in the atypical leukemia proved to be somewhat smaller than those of the typical acute leukemia. 2) The mean value of laveling index with (3)H-thymidine of the blasts in the bone marrow of the former group was 6.4% , while that of the latter was 12.9% . 3) The growth pattern of the bone marrow tissue from the 5 patients with atypical leukemia was as follows: The bone marrow explants from these patients were generally hypoplastic, consisting of an increase of fat cells intermingled with several foci scattered made of leukemic blasts. The growth zone revealed much lower cell density than that of the typical acute leukemia. The margin of the growth zone, however, sharply bordered and similar to the pattern of typical acute leukemia. Cells observed predominantly in the growth zone composed of immature leukemic cells and mature lymphocytes throughout the culture period of 24-48 hours. From these results, it is assumed that most of leukemic blasts in the bone marrow of the patients with atpical leukemia are dormant cells, i.e. belong to a nondividing compartment, and reduced multiplication rate is closely related to their mild clinical courses.
Thymidine
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Pathogenesis of atypical leukemia (hypoplastic leukemia and smoldering acute leukemia) is still unknown. The author intended to find the factors inducing its unique clinical course by comparing 5 cases of atypical leukemia with the same numder of typical acute leukemia with respect to their blasts cell size, laveling index with 3H-thymidine and pattern of tissue growth by the bone marrow culture method devised by us. And obtained the following results.1) The size of 100 blasts chosen randomely out of the bone marrow smear prepared from 5 cases of atypical leukemia was compared with those of typical acute leukemia. The mean value of the former group was 41.9±12.3, while that of the latter was 61.4±16.7. Therefore, the size of blasts in the atypical leukemia proved to be somewhat smaller than those of the typical acute leukemia.2) The mean value of laveling index with 3H-thymidine of the blasts in the bone marrow of the former group was 6.4%, while that of the latter was 12.9%.3) The growth pattern of the bone marrow tissue from the 5 patients with atypical leukemia was as follows: The bone marrow explants from these patients were generally hypoplastic, consisting of an increase of fat cells intermingled with several foci scattered made of leukemic blasts. The growth zone revealed much lower cell density than that of the typical acute leukemia. The margin of the growth zone, however, sharply bordered and similar to the pattern of typical acute leukemia. Cells observed predominantly in the growth zone composed of immature leukemic cells and mature lymphocytes throughout the culture period of 24-48 hours.From these results, it is assumed that most of leukemic blasts in the bone marrow of the patients with atpical leukemia are “dormant cells”, i.e. belong to a nondividing compartment, and reduced multiplication rate is closely related to their mild clinical courses.
Childhood leukemia
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The objective of this study was to investigate the expression and function of indoleamine 2, 3-dioxygenase (IDO) in leukemia. The IDO expressions in human acute monocyte leukemia (M(5)) and acute lymphocyte leukemia (ALL) were detected by immunofluorescence staining. Constructed leukemia mouse model was used to observe whether the IDO inhibitor, 1-methyl tryptophan (1-MT), has any effect in treating leukemia. The experimental group were fed with 1-MT solution every day while the mice in control group had no further treatment. The results showed that the average ratios of IDO expression were 29.4 +/- 11.2% in M(5) patients and 24.7 +/- 7.96% in ALL patients respectively. After statistical test, IDO expression level in leukemia cells was significantly higher than that of normal mononuclear cells. The tumor decreased gradually in mice treated with 1-MT. At the terminal point of the experiment (88 days after vaccination), the average survival time in the experimental group was 42.3 days while the mice in control group only lived 15.1 days in average, which difference was statistically significant (P < 0.05). Some of the leukemia mice in the experimental group long-term survived without tumor (more than three months after vaccination). It is concluded that human acute monocyte leukemia (M(5)) and acute lymphocyte leukemia (ALL) express IDO, and both can be treated by 1-MT in mice.
Indoleamine 2,3-dioxygenase
Acute monocytic leukemia
Monocyte
Acute myelomonocytic leukemia
Monocytic leukemia
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Autophagy plays an important dual role in the occurrence and development of acute leukemia, inducing the apoptosis of leukemia cells to suppress the development of acute leukemia, and protecting the leukemia cells to sustain the survival and to resist the apoptosis induced by chemotherapy drugs. Some studies have showed that the drug sensitivity of acute leukemia cells can be improved by regulating autophagy to induce the apoptosis of leukemia cells, and thus, regulating autophagy is expected to be an effective therapeutic strategy of refractory/relapsed acute leukemia. This article reviews the recent progress of autophagy and acute leukemia treatment.
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Autophagy; Acute leukemia; Drug resistance, neoplasm
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Pathogenesis
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Objective:To investigate the expression of MMP-2 and MMP-9 in acute leukemia and normal control and explore the relationship among MMP-2、MMP-9 and leukemia pathogenesis and infiltration.Method:The expression of MMP-2 and MMP-9 in bone marrow cells of untreated acute leukemia, relapse stage of acute leukemia, complete remission (CR) stage of acute leukemia and normal control were examined by in situ hybridization.Result:The positive rate of MMP-2 and MMP-9 in untreated, especially with infiltration and relapse stage of acute leukemia are significantly higher than that in CR stage of acute leukemia and normal control, the positive rate of MMP-2 and MMP-9 in untreated acute lymphoblastic leukemia(ALL) and acute nonlymphoblastic leukemia (ANLL) (M_4+M_5)group are significantly higher than that in ANLL (non M_4+M_5 )group.Conclusion:MMP-2 and MMP-9 may play an important role in leukemia pathogenesis and infiltration by enhancing the degradation of ECM.
Infiltration (HVAC)
Pathogenesis
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Chronic leukemia
White blood cell
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Neutrophils, the most abundant white blood cells in humans, play pivotal roles in innate immunity, rapidly migrating to sites of infection and inflammation to phagocytose, neutralize, and eliminate invading pathogens. Neutrophil extracellular trap (NET) formation is increasingly recognized as an essential rapid innate immune response, but when dysregulated, it contributes to pathogenesis of sepsis and immunothrombotic disease.
Neutrophil Extracellular Traps
Pathogenesis
Trap (plumbing)
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1. The Impact of Treatment on the Natural History of Acute Leukemia.- 2. Experimental Rationale for Therapy in the Treatment of Acute Leukemia.- 3. Clinical Laboratory Methods Used for the Classification of Acute Leukemia.- 4. HTLV-II and Human Leukemia.- 5. Oncogene Expression and Arrangement in Human Leukemia.- 6. Clonal Variation and Phenotypic Progression in Retrovirus Transformed Leukemia Cells.- 7. Chemotherapeutic Agents as Differentiation Inducers.- 8. Modes of Drug Resistance in Acute Leukemias.- 9. The Evolution of Therapy for Acute Lymphatic Leukemia in Children.- 10. Prognostic Factors in Childhood Acute Lymphoblastic Leukemia: Correlation with Treatment Response.- 11. Clinical Trials in Adult ANLL: An Overview.- 12. Allogeneic Marrow Transplantation for Acute Nonlymphoblastic Leukemia in Adults.- 13. Treatment Choices for Patients with Acute Nonlymphocytic Leukemia in Remission: Chemotherapy and Bone Marrow Transplantation.- 14. Autologous Bone Marrow Transplantation in Acute Leukemia.- 15. Treatment of Leukemia and Lymphoma with Biological Response Modifiers.- 16. Transfusion Therapy for the Support of Leukemia Patients.- 17. Leukemia:Hemorrhagic and Thrombotic Complications.
Acute lymphocytic leukemia
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To investigate the expression levels of serum sICAM-1 and their clinical significances in patients with hyperleukocytic acute leukemia(HLAL).The serum levels of sICAM-1 in 30 hyperleukocytic acute leukemia and 20 non-hyperleukocytic acute leukemia were detected by ELISA,compared with 20 healthy persons as the control group.The expression of sICAM-1 in patients with hyperleukocytic acute leukemia and non-hyperleukocytic acute leukemia were significantly higher than those in control group,expecially in hyperleukocytic acute leukemia.Over expression of sICAM-1 may play a key role in the genesis and progression of hyperleukocytic acute leukemia.
Clinical Significance
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