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2.
Immunobiology ; 222(2): 343-349, 2017 02.
Article in English | MEDLINE | ID: mdl-27682013

ABSTRACT

RATIONALE: Siglec-8 is a surface receptor predominantly expressed on human eosinophils where its ligation induces reactive oxygen species (ROS) formation and cell death. Since Siglec-8 has intracellular tyrosine-based motifs, we hypothesized that Src family kinases (SFKs) are involved in ROS formation and cell death induced by Siglec-8 engagement. METHODS: Human peripheral blood eosinophils were purified and incubated with anti-Siglec-8 monoclonal antibodies (mAb, agonist), IL-5, and SFK pharmacological inhibitors. We focused on Siglec-8-induced cell death in short-term IL-5-activated cells leading to a regulated necrosis-type cell death. ROS production was determined by dihydrorhodamine (DHR) 123 labeling and flow cytometry, or by chemiluminescence using Amplex red. Activation of SFK was determined using phospholuminex and Western blotting. RESULTS: In order to determine cellular localization of ROS production, we measured intra and extracellular ROS. While an ETosis stimulus (calcium ionophore A23187) led to extracellular ROS (ecROS) production, Siglec-8-engagement in short-term IL-5 activated cells led to intracellular ROS (icROS) accumulation. Consistently, inhibition of extracellular ROS by catalase inhibited ETosis, but not IL-5-primed Siglec-8-induced cell death. In order to determine signaling events for Siglec-8, we performed Western blotting and found SFK phosphorylation in lysates from eosinophils stimulated with anti-Siglec-8 mAb±IL-5. In order to identify which SFKs were involved, we used the phospholuminex assay and found increased levels of phosphorylated Fgr in the cytoplasmic fraction of cells co-stimulated with anti-Siglec-8 and IL-5 for 3 hours compared with cells stimulated with IL-5 alone. To test the involvement of SFKs in ROS production and cell death, we used SFK inhibitors PP2 and dasatinib, both of which completely inhibited eosinophil ROS production and cell death induced by anti-Siglec-8 and IL-5 co-stimulation. CONCLUSION: Siglec-8 engagement in short-term IL-5-activated eosinophils causes icROS production and SKF phosphorylation, and both are essential in mediating Siglec-8-induced cell death.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, B-Lymphocyte/metabolism , Eosinophils/metabolism , Lectins/metabolism , Reactive Oxygen Species/metabolism , src-Family Kinases/metabolism , Cell Death , Cells, Cultured , Eosinophils/drug effects , Eosinophils/immunology , Humans , Interleukin-5/metabolism , Interleukin-5/pharmacology , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , src-Family Kinases/antagonists & inhibitors
3.
Mol Med Rep ; 14(6): 5077-5083, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27779714

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by structural and/or functional impairment of cilia throughout the whole body. Early diagnosis of PCD is important for the prevention of long­term sequelae, however early diagnosis is a challenge due to the phenotypic heterogeneity of PCD. In the current study, the patient with PCD was diagnosed at nine years old following several efforts to control intractable airway symptoms. The patient experienced a chronic productive cough beginning in early childhood and had multiple episodes of pneumonia and otitis media with effusion and sinusitis. No situs inversus or other heterotaxias were reported. Serial chest X­rays exhibited persistent atelectasis and bronchiectasis in the right middle lobe. When the patient was nine years old, electron microscopy of his cilia and genetic analysis were conducted. Electron microscopy of a biopsy specimen from the nasal mucosa indicated loss of the outer dynein arms. Whole­exome analysis of the genome demonstrated the presence of compound heterozygous mutations in DNAH5: NM_001369.2:c.5983C>T, p.Arg1995X in exon 36 and NM_001369.2:c.9101delG, p.Gly3034ValfsX22 in exon 54; neither of which have been previously reported in the literature in a Japanese patient. Notably, this case is, to the best of our knowledge, the first reported case of PCD caused by the DNAH5 mutation in a Japanese patient.


Subject(s)
Axonemal Dyneins/genetics , Kartagener Syndrome/genetics , Mutation , Child , DNA Mutational Analysis , Exome , Heterozygote , High-Throughput Nucleotide Sequencing , Humans , Kartagener Syndrome/diagnosis , Male , Pedigree , Radiography, Thoracic , Tomography, X-Ray Computed
4.
Pediatr Int ; 56(1): 119-22, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24548200

ABSTRACT

Pulmonary veno-occlusive disease (PVOD) is a rare chronic lung disease that is difficult to diagnose due to non-specific clinical findings. Little is known about the pathogenesis of PVOD. Reported herein is the case of an 11-year-old girl who initially presented with 'bat-wing' shadows on chest radiography. This finding, coupled with prominent hemosiderosis in bronchoalveolar lavage fluid, initially led to a misdiagnosis of idiopathic pulmonary hemosiderosis. Oral prednisolone dramatically improved signs and symptoms initially, but her condition then gradually deteriorated during maintenance therapy with corticosteroids and other immunosuppressants. PVOD was suspected but not confirmed owing to a lack of hallmark radiographic findings and contraindications for lung biopsy. Three years later, while arranging for lung transplantation, the patient experienced sudden onset of fatal massive pulmonary edema. PVOD was confirmed at autopsy. This case provides insights regarding an unfamiliar presentation of PVOD and may help physicians to avoid diagnostic pitfalls.


Subject(s)
Biopsy/methods , Pulmonary Veno-Occlusive Disease/diagnosis , Tomography, X-Ray Computed/methods , Autopsy , Child , Diagnosis, Differential , Fatal Outcome , Female , Humans , Respiratory Function Tests
6.
PLoS One ; 8(6): e68143, 2013.
Article in English | MEDLINE | ID: mdl-23840825

ABSTRACT

BACKGROUND: Siglec-F and Siglec-8 are functional paralog proapoptotic cell surface receptors expressed on mouse and human eosinophils, respectively. Whereas Siglec-8 mediated death involves caspases and/or reactive oxygen species (ROS) generation and mitochondrial injury, very little is known about Siglec-F-mediated signaling and apoptosis. Therefore the objective of the current experiments was to better define apoptosis pathways mediated by Siglec-F and Siglec-8. Given that Siglec-F-induced apoptosis is much less robust than Siglec-8-induced apoptosis, we hypothesized that mechanisms involved in cell death via these receptors would differ. METHODS: Consequences of engagement of Siglec-F on mouse eosinophils were studied by measuring ROS production, and by performing apoptosis assays using eosinophils from normal, hypereosinophilic, NADPH oxidase-deficient, src homology domain-containing protein tyrosine phosphatase (SHP)-1-deficient, and Lyn kinase-deficient mice. Inhibitors of caspase and Src family kinase activity were also used. RESULTS: Engagement of Siglec-F induced mouse eosinophil apoptosis that was modest in magnitude and dependent on caspase activity. There was no detectable ROS generation, or any role for ROS, NADPH oxidase, SHP-1, or Src family kinases in this apoptotic process. CONCLUSIONS: These data suggest that Siglec-F-mediated apoptosis is different in both magnitude and mechanisms when compared to published data on Siglec-8-mediated human eosinophil apoptosis. One likely implication of this work is that models targeting Siglec-F in vivo in mice may not provide identical mechanistic predictions for consequences of Siglec-8 targeting in vivo in humans.


Subject(s)
Antigens, Differentiation, Myelomonocytic/metabolism , Apoptosis/physiology , Caspases/metabolism , Eosinophils/metabolism , Eosinophils/physiology , Animals , Lectins/metabolism , Mice , Mice, Inbred C57BL , NADPH Oxidases/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Reactive Oxygen Species/metabolism , Sialic Acid Binding Immunoglobulin-like Lectins , src-Family Kinases/metabolism
7.
J Allergy Clin Immunol ; 132(2): 437-45, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23684072

ABSTRACT

BACKGROUND: Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is expressed on human eosinophils, where its ligation induces cell death. Paradoxically, Siglec-8-mediated cell death is markedly enhanced by the presence of the activation and survival factor IL-5 and becomes independent of caspase activity. OBJECTIVE: In this report we investigate the mechanism of Siglec-8-mediated cell death in activated eosinophils. METHODS: Human peripheral blood eosinophils were treated with agonistic anti-Siglec-8 antibody and IL-5, and cell death was determined by using flow cytometry and morphology. Phosphorylation of mitogen-activated protein kinase (MAPK) was determined by using phosphoLuminex, flow cytometry, and Western blotting. Reactive oxygen species (ROS) accumulation was determined by using dihydrorhodamine fluorescence. RESULTS: Costimulation with anti-Siglec-8 and IL-5 significantly increased the rate and proportion of cell death by means of necrosis accompanied by granule release compared with that seen after stimulation with anti-Siglec-8 alone, in which apoptosis predominated. Together with the caspase-independent mode of cell death in costimulated cells, these findings suggest the activation of a specific and distinct biochemical pathway of cell death during anti-Siglec-8/IL-5 costimulation. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and MAPK-ERK kinase (MEK) 1 was significantly enhanced and sustained in costimulated cells compared with that seen in cells stimulated with IL-5 alone; anti-Siglec-8 alone did not cause ERK1/2 phosphorylation. MEK1 inhibitors blocked anti-Siglec-8/IL-5-induced cell death. ROS accumulation was induced by Siglec-8 ligation in a MEK-independent manner. In contrast, an ROS inhibitor prevented the anti-Siglec-8/IL-5-induced enhancement of ERK phosphorylation and cell death. Exogenous ROS mimicked stimulation by anti-Siglec-8 and was sufficient to induce enhanced cell death in IL-5-treated cells. Collectively, these data suggest that the enhancement of ERK phosphorylation is downstream of ROS generation. CONCLUSIONS: In activated eosinophils ligation of Siglec-8 leads to ROS-dependent enhancement of IL-5-induced ERK phosphorylation, which results in a novel mode of biochemically regulated eosinophil cell death.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, B-Lymphocyte/metabolism , Cell Death/drug effects , Eosinophils/immunology , Interleukin-5/immunology , Lectins/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Mitogen-Activated Protein Kinases/metabolism , Reactive Oxygen Species/pharmacology , Antigens, CD/genetics , Antigens, Differentiation, B-Lymphocyte/genetics , Apoptosis/drug effects , Cells, Cultured , Enzyme Activation/drug effects , Eosinophils/physiology , Humans , Lectins/genetics , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinases/drug effects , Mitogen-Activated Protein Kinases/genetics , Phosphorylation , Reactive Oxygen Species/metabolism
8.
Pediatr Blood Cancer ; 56(5): 853-5, 2011 May.
Article in English | MEDLINE | ID: mdl-21370423

ABSTRACT

A 3-year-old male presented with Chlamydia pneumoniae infection-related hemophagocytic lymphohistiocytosis (HLH). The patient developed an episode of HLH with severe skin eruption following C. pneumoniae pneumonia. Symptoms responded to steroid/cyclosporine A therapy, but the patient slowly lost consciousness and developed systemic flaccid paralysis. He was diagnosed with encephalitis/myelitis by brain and spinal MRI. Neurological symptoms and signs gradually resolved. We thought that the immune response to C. pneumoniae infection triggered the development of HLH, associated with unusual neurological complications. This report describes a novel case of C. pneumoniae-associated HLH and with poliomyelitis like flaccid paralysis.


Subject(s)
Chlamydia Infections/complications , Lymphohistiocytosis, Hemophagocytic/etiology , Paralysis/etiology , Poliomyelitis/etiology , Anti-Inflammatory Agents/therapeutic use , Child, Preschool , Chlamydia Infections/drug therapy , Chlamydophila pneumoniae/pathogenicity , Cyclosporine/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/pathology , Magnetic Resonance Imaging , Male , Paralysis/drug therapy , Paralysis/pathology , Poliomyelitis/drug therapy , Poliomyelitis/pathology , Poliovirus/pathogenicity , Prednisolone/therapeutic use
9.
Leuk Lymphoma ; 49(5): 965-73, 2008 May.
Article in English | MEDLINE | ID: mdl-18464116

ABSTRACT

Ikaros is an essential regulator of lymphocyte differentiation. Mice transgenic for the Ikaros dominant negative (DN) mutation rapidly develop lymphoid malignancies. Various human leukemias have also been reported to express Ikaros DN isoforms, but its role in leukemogenesis is yet to be defined. We demonstrate that overexpressed Ikaros DN (Ik6) prolonged the survival of two different murine pro-B cell lines in cytokine deprived condition, and this was associated with increased expression of Bcl-xl. A survey of the upstream controller(s) of Bcl-xl expression revealed Ik6 overexpression enhanced the phosphorylation of JAK2 and STAT5. Interestingly, the Ik6 expressing cell lines showed reduced expression of B-cell differentiation surface marker CD45R (B220), which is also known as a JAK2 inhibitor. Although further evaluation with human clinical materials are required, these results propose a putative role of Ik6 in the development of B-lineage acute lymphoblastic leukemia, by activating the JAK2-STAT5 pathway and thus stimulating the production of Bcl-xl.


Subject(s)
Ikaros Transcription Factor/physiology , Janus Kinase 2/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor Cells, B-Lymphoid/cytology , STAT5 Transcription Factor/metabolism , bcl-X Protein/biosynthesis , Animals , Apoptosis Regulatory Proteins , Cell Line , Cell Survival , Humans , Ikaros Transcription Factor/genetics , Interleukin-3 , Mice , Protein Isoforms/physiology , Transfection , Up-Regulation
11.
Leuk Lymphoma ; 46(5): 729-35, 2005 May.
Article in English | MEDLINE | ID: mdl-16019511

ABSTRACT

We described the cerebral thrombotic complications developed in 2 adolescent patients treated with L-asparaginase-containing regimens. For determining risk factors, we retrospectively analysed hemostatic markers in 19 pediatric patients with leukemia or lymphoma who were treated with either 1 of the 2 L-asparaginase-containing regimens; 11 were treated with VLP1 and the remaining 8 were treated with the VLAD protocol. The data indicated that low coagulation factors in association with increased plasma D-dimer levels during or post-L-asparaginase administration combined with fresh frozen plasma infusion might have activated coagulation processes in these patients. Careful management is required to prevent such episodes in patients with markedly decreased coagulation factors and increased D-dimer levels following L-asparaginase administration.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Asparaginase/adverse effects , Intracranial Thrombosis/chemically induced , Lymphoma, Non-Hodgkin/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antithrombin III/administration & dosage , Asparaginase/administration & dosage , Child , Child, Preschool , Female , Fibrin Fibrinogen Degradation Products/biosynthesis , Humans , Infant , Intracranial Thrombosis/blood , Lymphoma, Non-Hodgkin/blood , Male , Plasma , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Retrospective Studies , Risk Factors
12.
Int J Hematol ; 80(5): 410-5, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15646651

ABSTRACT

Hemoglobin (Hb) Bristol-Alesha is caused by a GTG --> ATG mutation at codon 67 in the Hb beta chain, resulting in abnormal beta globin chains with mutated molecules from normal beta67 valine (Val) to beta67 methionine (Met) or beta67 aspartate (Asp). We describe a Japanese child with this rare hemoglobinopathy and a very unstable Hb molecule phenotype. The diagnosis of hemolytic anemia was made when the patient was 6 months of age. Development of marked splenomegaly necessitated red blood cell transfusions twice a month. After splenectomy when the patient was 4 years of age, laboratory findings of hemolytic anemia became more prominent. Specific abnormal Hb molecules initially were not detected, and the alpha/beta globin synthesis ratio was abnormal at 2.22. After splenectomy, we identified the presence of abnormal beta-globin chains with a beta67Val:beta67Met:beta67Asp molecule ratio of 74:11:15. We speculate that the high fraction of the beta67Met molecule in this patient, compared with that in previously reported cases, caused extreme Hb instability, which resulted in thalassemic hyperunstable hemoglobinopathy and very severe clinical findings.


Subject(s)
Amino Acid Substitution/genetics , Hemoglobinopathies/genetics , Hemoglobins, Abnormal/genetics , Point Mutation/genetics , Anemia, Hemolytic/etiology , Anemia, Hemolytic/genetics , Anemia, Hemolytic/metabolism , Anemia, Hemolytic/pathology , Blood Transfusion , DNA Mutational Analysis , Hemoglobinopathies/complications , Hemoglobinopathies/metabolism , Hemoglobinopathies/pathology , Hemoglobinopathies/therapy , Hemoglobins, Abnormal/metabolism , Humans , Infant , Male , Prognosis , Splenectomy , Splenomegaly/etiology , Splenomegaly/pathology , Thalassemia/etiology , Thalassemia/genetics , Thalassemia/metabolism , Thalassemia/pathology
13.
Clin Rheumatol ; 22(6): 484-6, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14677035

ABSTRACT

An 11-year-old girl presented with fever and a large cervical lymphadenopathy. Indicators of inflammation were remarkable: she had extremely high levels of serum interleukin-6 (IL-6) (398 pg/ml) in addition to hypergammaglobulinemia and hypoalbuminemia. Computed tomography (CT) revealed swollen systemic lymph nodes. Two weeks after the onset of symptoms she developed polyarthralgia. Biopsy of the cervical lymph node revealed massive infiltration of plasma cells without hyaline vascular changes. She was diagnosed with systemic juvenile idiopathic arthritis (JIA). The patient's symptoms and hypercytokinemia disappeared soon after corticosteroid treatment was started. This case demonstrates that overproduction of IL-6 is common to systemic JIA and multicentric Castleman's disease.


Subject(s)
Arthritis, Juvenile/diagnosis , Castleman Disease/diagnosis , Lymph Nodes/pathology , Arthritis, Juvenile/drug therapy , Biopsy, Needle , Castleman Disease/drug therapy , Child , Diagnosis, Differential , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Immunohistochemistry , Prednisolone/administration & dosage , Risk Assessment , Severity of Illness Index , Tomography, X-Ray Computed , Treatment Outcome
14.
Haematologica ; 88(11): 1238-44, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14607752

ABSTRACT

BACKGROUND AND OBJECTIVES: The glutathione-S-transferase (GST) polymorphism may affect the outcome of treatment of leukemia because GSTs play an important role in detoxifying the chemotherapeutic agents used to kill leukemia cells. However, results of previous reports have been controversial. This study was undertaken to clarify the influence of GST polymorphism on the outcome of childhood B-precursor acute lymphoblastic leukemia (ALL). DESIGN AND METHODS: Eighty-two patients with childhood B-precursor ALL treated during 1988-1999 with our ALL protocol (median follow-up time 89.5 months, range 31 -169 months) were examined for GST gene patterns. The effect of GSTM1 and GSTT1 deletion genotypes on the clinical features and therapeutic results was analyzed. RESULTS: All patients attained complete remission but 12 had an early relapse (within 30 months of the initiation of treatment). In univariate analysis, early relapse of ALL was correlated significantly with the presence of the t(9;22)(q34;q11) cytogenetic abnormality (p=0.0003), high white blood cell counts (p=0.015) and double null genotype (p=0.027). Multivariate analysis revealed that the GST double null genotype was the only significant independent predictor of early relapse (p=0.018). INTERPRETATION AND CONCLUSIONS: The simultaneous deletion of both the GSTM1 and GSTT1 genes is more predictive than any other parameter of early relapse of childhood B-precursor ALL.


Subject(s)
Glutathione Transferase/physiology , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Disease-Free Survival , Drug Resistance, Neoplasm/genetics , Female , Follow-Up Studies , Genotype , Glutathione Transferase/deficiency , Glutathione Transferase/genetics , Humans , Infant , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Prognosis , Survival Rate , Translocation, Genetic
15.
Br J Haematol ; 122(6): 1009-13, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12956773

ABSTRACT

We report the case of a 3-year-old Japanese boy with phosphoglycerate kinase 1 (PGK1) deficiency (Online Mendelian Inheritance in Man entry 311800). The patient had anaemia and jaundice at birth, necessitating exchange transfusions for 2 d. After one red blood cell transfusion at age 2 months, his Hb level was 8-9 g/dl, his reticulocyte counts were 300-500 x 109/l, and his total bilirubin level was 25.65-42.75 micro mol/l. The patient suffered two episodes of respiratory infection-associated haemolytic crisis and rhabdomyolysis during early infancy. At age 3.0 years, his developmental milestones (developmental quotients measured using the Tsumori-Inage methods) score was 49% (normal 74-131%), and his height was below average by -2.0 standard deviations. The diagnosis of PGK1 deficiency was made based on his remarkably low (< 10% of normal) erythrocyte PGK enzyme activity level and the identification of a novel missense (1060G-->C) PGK1 gene mutation. This mutation results in the Ala-353Pro amino acid substitution, which has been designated PGK Kyoto. The patient developed the full clinical symptoms of PGK1 deficiency including haemolytic anaemia, myopathy, central nervous system disorder and growth retardation, which is unusual.


Subject(s)
Anemia, Hemolytic, Congenital/genetics , Developmental Disabilities/genetics , Mutation, Missense , Phosphoglycerate Kinase/genetics , Rhabdomyolysis/genetics , Child, Preschool , Humans , Male , Models, Molecular , Phosphoglycerate Kinase/deficiency
17.
Blood ; 99(4): 1350-5, 2002 Feb 15.
Article in English | MEDLINE | ID: mdl-11830486

ABSTRACT

While studying Ikaros proteins in childhood acute myeloid leukemia (AML), Ikaros isoform 6 (Ik6) expression was detected in 7 of 10 cases of M4 and M5 leukemia, but in none of the remaining French-American-British subtypes (M2, 8 cases; M7, 6 cases). The spliced Ikaros isoforms 4 to 8 (Ik4-8) suppress the function of full-length Ik1 or Ik2 in a dominant-negative manner, owing to their reduced numbers of DNA binding sites. Thus, dominant-negative Ikaros isoforms may inhibit the normal transcriptional regulation of hematopoietic cell development. To clarify the function of Ik6 in developing blood cells, this isoform was transiently transfected into an Ik2(+), interleukin-3 (IL-3)-dependent 32D murine myeloid precursor cell line and studied the expression of Bcl-2 family proteins in relation to in vitro cell growth, using a tetracycline-inducible TREx system. The possibility of aberrant cell regulation due to Ikaros functional changes was examined by cotransfecting both Ik2 and Ik6 into Ikaros/Aiolos/Helios triple-negative Cos-7 cells. The results demonstrated IL-3-independent growth by Ik6-transfected 32D clones coincident with up-regulation of the antiapoptotic protein Bcl-XL. Up-regulation of Bcl-XL, but not of other Bcl-2 family proteins, was associated with the suppression of functional Ik2 by Ik6 in a dominant-negative fashion. Thus, the pathogenesis of myelomonocytic/monocytic AML may involve aberrant regulation of apoptosis due to unscheduled expression of the Ik6 isoform.


Subject(s)
DNA-Binding Proteins , Leukemia, Monocytic, Acute/genetics , Leukemia, Myelomonocytic, Acute/genetics , Transcription Factors/physiology , Adolescent , Animals , Apoptosis/drug effects , Blood Cells/metabolism , Blood Cells/pathology , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , COS Cells , Cell Transformation, Neoplastic/chemically induced , Cell Transformation, Neoplastic/metabolism , Child , Child, Preschool , Female , Gene Expression/drug effects , Gene Expression Regulation , Hematopoiesis/drug effects , Humans , Ikaros Transcription Factor , Infant , Leukemia, Monocytic, Acute/etiology , Leukemia, Myelomonocytic, Acute/etiology , Male , Mice , Protein Isoforms/genetics , Protein Isoforms/pharmacology , Protein Isoforms/physiology , Proto-Oncogene Proteins c-bcl-2/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Transcription Factors/analysis , Transcription Factors/genetics , Transfection , Tumor Cells, Cultured , Up-Regulation/drug effects , bcl-X Protein
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