ABSTRACT
Although salvage therapy with rituximab is effective in some cases of immune-mediated thrombotic thrombocytopenic purpura (iTTP) refractory to standard plasma exchange (PEX) and glucocorticoid treatment or relapsed after treatment, protocols to address the subsequent high recurrence rate have not been established. We describe the use of cyclosporine (CSA) to prevent recurrence in a patient with iTTP relapse after rituximab therapy, and present a literature review. A 24-year-old woman was diagnosed with iTTP and initially received PEX and high-dose methylprednisolone therapy. However, weekly rituximab therapy was also needed for inhibitor boosting to achieve additional immunosuppression during the initial treatment. Although the patient achieved clinical remission after weekly rituximab therapy, iTTP relapsed twice when glucocorticoids were tapered, and was treated with a triplet regimen consisting of PEX, high-dose methylprednisolone, and weekly rituximab. CSA was administered along with glucocorticoids as prophylaxis against iTTP relapse. The additional CSA therapy successfully maintained iTTP remission and allowed reduction of the corticosteroid dose. Our findings demonstrate that prophylactic CSA can potentially prevent iTTP recurrence in patients with a history of multiple relapses. Data from more cases must be accumulated to establish a useful prophylactic therapy for iTTP that is refractory even to rituximab.
Subject(s)
Cyclosporine , Immunosuppressive Agents , Purpura, Thrombotic Thrombocytopenic , ADAMTS13 Protein , Adult , Cyclosporine/therapeutic use , Female , Humans , Immunosuppressive Agents/therapeutic use , Methylprednisolone/therapeutic use , Plasma Exchange , Purpura, Thrombotic Thrombocytopenic/drug therapy , Recurrence , Rituximab/therapeutic use , Young AdultABSTRACT
UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.
Subject(s)
Hematologic Neoplasms , Hematopoietic Stem Cell Transplantation , Bone Marrow Transplantation , Genotype , Hematologic Neoplasms/genetics , Hematologic Neoplasms/therapy , Humans , Membrane Transport Proteins , Polymorphism, Single NucleotideABSTRACT
OBJECTIVES: Reticulated platelets circulating in the blood reflect megakaryopoietic activity and platelet turnover and can be automatically and low-invasively measured as the immature platelet fraction (IPF) using a Sysmex XN hematocytometer. The present study retrospectively investigated whether or not the IPF can predict the treatment response to corticosteroids in adult patients with primary immune thrombocytopenia (ITP). METHODS: Forty-six patients who had been newly diagnosed with primary treatment-naïve ITP and started treatment with corticosteroids were analyzed. RESULTS: Among the 46 primary ITP patients, 33 (72%) responded to the treatment and 13 (28%) did not. The percentage of IPF (IPF%) among the nonresponders was significantly lower than that of the responders (6.6 vs. 16.0%; p < 0.001). In the receiver operating characteristics analysis, the optimum IPF% cut-off value for predicting the treatment response was 12%, with a specificity of 85% and a sensitivity of 76%. CONCLUSIONS: Our findings thus suggest that measuring the IPF% as a surrogate of reticulated platelets is useful to identify patients likely to respond to corticosteroids.
Subject(s)
Adrenal Cortex Hormones/therapeutic use , Blood Platelets/cytology , Platelet Transfusion , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Adult , Aged , Aged, 80 and over , Area Under Curve , Female , Humans , Male , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/drug therapy , ROC Curve , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Introduction: Due to an increased incidence of copper deficiency, we investigated adult patients who had low serum levels of copper with cytopenia at our hospital from March 2014 to March 2021. Methods: We retrospectively reviewed the clinical data of patients who had been diagnosed with cytopenia due to copper deficiency at the Aichi Medical University Hospital from March 2014 to March 2021. Results: In the 15 patients with cytopenia secondary to low serum copper level, 11 had cytopenia of two to three lineages; three (27%) had pancytopenia, and eight (73%) had bicytopenia. Of the 15 patients, nine (60%) underwent bone marrow examinations; three (30%) showed typical morphologic features associated with copper deficiency, such as multiple clear cytoplasmic vacuoles in erythroblasts and myeloid cells, and three (30%) showed dysplastic features as observed in myelodysplastic syndrome. Among the 14 (93%) patients who were treated with copper supplements, had cessation of zinc supplements, or both, 11 (73%) and eight (53%) showed normal copper levels and hematological improvement, respectively. Conclusion: Copper deficiency is more common than expected and should be considered in patients with unexplained cytopenia.
ABSTRACT
Although patients with cancer and immunosuppression are at a risk of functional hyposplenism, how to detect it promptly remains unclear. Since hyposplenism allows erythrocytes with nuclear remnants (Howell-Jolly bodies [HJBs]) to appear in the peripheral blood, HJB detection by a routine microscopic examination may help identify patients with functional hyposplenism. This prospective study was thus performed to determine the underlying diseases in patients who presented with HJBs. Of 100 consecutive patients presenting with HJBs, 73 had a history of splenectomy. The remaining 27 had hematologic cancer (n = 6, 22%), non-hematologic cancer (n = 8, 30%), hepatic disorders (n = 4, 15%), premature neonates (n = 3, 11%), hemolytic anemia (n = 2, 7%), autoimmune disorders (n = 2, 7%) and miscellaneous diseases (n = 2, 7%), and their prior treatments included chemotherapy (n = 8, 30%), steroids (n = 7, 26%) and molecular-targeted therapy (n = 3, 11%). Among the 27 patients, 22 had computed tomography scans available: 3 (14%) had underlying diseases in the spleen, and the remaining 19 (86%) were all found to have a decreased splenic volume, including 11 (50%) with more than 50% of the ideal value. The present findings suggest that HJB detection identifies patients with potentially functional hyposplenism who should receive appropriate interventional treatment, such as vaccination and prophylactic antibiotics.
Subject(s)
Erythrocyte Inclusions/pathology , Erythrocyte Inclusions/ultrastructure , Erythrocytes/cytology , Erythrocytes/pathology , Splenic Diseases/blood , Splenic Diseases/diagnosis , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Prospective Studies , Splenic Diseases/etiology , Young AdultABSTRACT
We report the case of a patient with fulminant pneumococcal infection along with the presence of Howell-Jolly bodies (HJBs) and splenic hypoplasia at the onset. A 71-year-old man developed fever during outpatient chemotherapy for IgG-κ multiple myeloma and was diagnosed with septic shock due to invasive pneumococcal infection. HJBs were observed on peripheral blood smears at this visit. Computed tomography revealed marked hypoplasia of spleen, suggesting the presence of hyposplenic function. Antibacterial therapy was initiated and the pneumococcal infection was cured; however, there was no notable change in his splenic hypoplasia. Splenic hypoplasia can be associated with fatal infections; hence, care should be taken when it is found in the elderly and in patients with cancer and those receiving immunosuppressive treatment. Even today, when automated hematology analyzers have become common, not all patients with hematological diseases have peripheral blood smears checked with a normal optical microscope. This study suggests that HJBs may be useful for simple and rapid screening of splenic hypofunction. The importance of detecting HJBs in peripheral blood smears with a normal optical microscope should be re-recognized.
Subject(s)
Pneumococcal Infections , Splenic Diseases , Aged , Erythrocyte Inclusions , Hematologic Tests , Humans , Male , Primary Immunodeficiency Diseases , Spleen/abnormalitiesABSTRACT
Unbalanced translocation der(1;7)(q10;p10) is a characteristic chromosomal abnormality in myelodysplastic syndrome (MDS). The current study revealed that among 13 MDS patients with der(1;7)(q10;p10), seven cases with no apparent dysplasia also had low numbers of myeloblasts in the bone marrow and a 3-year survival rate of 86%; in contrast, the remaining six cases had a 3-year survival rate of 0% (P = .003). It was therefore suggested that MDS patients with der(1;7)(q10;p10) are classified into a distinct group with a favorable prognosis and another distinct group with a very poor prognosis.
ABSTRACT
Chromosome band 8q24 is the most frequently amplified locus in various types of cancers. MYC has been identified as the primary oncogene at the 8q24 locus, whereas a long noncoding gene, PVT1, which lies adjacent to MYC, has recently emerged as another potential oncogenic regulator at this position. In this study, we established and characterized a novel cell line, AMU-ML2, from a patient with diffuse large B-cell lymphoma (DLBCL), displaying homogeneously staining regions at the 8q24 locus. Fluorescence in situ hybridization clearly detected an elevation in MYC copy numbers corresponding to the homogenously staining region. In addition, a comparative genomic hybridization analysis using high-resolution arrays revealed that the 8q24 amplicon size was 1.4 Mb, containing the entire MYC and PVT1 regions. We also demonstrated a loss of heterozygosity for TP53 at 17p13 in conjunction with a TP53 frameshift mutation. Notably, AMU-ML2 cells exhibited resistance to vincristine, and cell proliferation was markedly inhibited by MYC-shRNA-mediated knockdown. Furthermore, genes involved in cyclin D, mTOR, and Ras signaling were downregulated following MYC knockdown, suggesting that MYC expression was closely associated with tumor cell growth. In conclusion, AMU-ML2 cells are uniquely characterized by homogenously staining regions at the 8q24 locus, thus providing useful insights into the pathogenesis of DLBCL with 8q24 abnormalities.
ABSTRACT
We examined the effects of diet nutrients on xenotransplanted leukemia cells, THP-1 or NB4. THP-1 tumors showed more growth when fed with high fat diet, while NB4 tumors grew more with high carbohydrate diet. Then, administration of 2-deoxyglucose (a glycolysis inhibitor) showed a significant antitumor effect on both tumors: NB4 tumor showed large necrotic areas, while THP-1 tumor did not, but had augmented expression of enzymes for fatty acid oxidation. 2-Deoxyglucose inhibited the growth of NB4 by cell death because main energy producing pathway (glycolysis) was abolished, while 2-deoxyglucose slowed the growth of THP-1 by shifting energy metabolism to fatty acid ß-oxidation.
Subject(s)
Antimetabolites/pharmacology , Cell Proliferation , Deoxyglucose/pharmacology , Diet , Dietary Supplements , Leukemia, Experimental/drug therapy , Animals , Blotting, Western , Energy Metabolism/drug effects , Female , Glycolysis/drug effects , Humans , Immunoenzyme Techniques , Leukemia, Experimental/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
The shift in energy metabolism from oxidative phosphorylation to glycolysis can serve as a target for the inhibition of cancer growth. Here, we examined the metabolic changes induced by 2-deoxyglucose (2-DG), a glycolysis inhibitor, in leukemia cells by metabolome analysis. NB4 cells mainly utilized glucose as an energy source by glycolysis and oxidative phosphorylation in mitochondria, since metabolites in the glycolytic pathway and in the tricarboxylic acid (TCA) cycle were significantly decreased by 2-DG. In THP-1 cells, metabolites in the TCA cycle were not decreased to the same extent by 2-DG as in NB4 cells, which indicates that THP-1 utilizes energy sources other than glucose. TCA cycle metabolites in THP-1 cells may be derived from acetyl-CoA by fatty acid ß-oxidation, which was supported by abundant detection of carnitine and acetylcarnitine in THP-1 cells. 2-DG treatment increased the levels of pentose phosphate pathway (PPP) metabolites and augmented the generation of NADPH by glucose-6-phosphate dehydrogenase. An increase in NADPH and upregulation of glutathione synthetase expression resulted in the increase in the reduced form of glutathione by 2-DG in NB4 cells. We demonstrated that a combination of 2-DG and inhibition of PPP by dehydroepiandrosterone (DHEA) effectively suppressed the growth of NB4 cells. The replenishment of the TCA cycle by fatty acid oxidation by carnitine palmitoyltransferase in THP-1 cells, treated by 2-DG, might be regulated by AMPK, as the combination of 2-DG and inhibition of AMPK by compound C potently suppressed the growth of THP-1 cells. Although 2-DG has been effective in preclinical and clinical studies, this treatment has not been fully explored due to concerns related to potential toxicities such as brain toxicity at high doses. We demonstrated that a combination of 2-DG and DHEA or compound C at a relatively low concentration effectively inhibits the growth of NB4 and THP-1 cells, respectively. These observations may aid in the identification of appropriate combinations of metabolic inhibitors at low concentrations which do not cause toxicities.
Subject(s)
Deoxyglucose/pharmacology , Energy Metabolism/drug effects , Leukemia/metabolism , AMP-Activated Protein Kinases/metabolism , Acetyl Coenzyme A/metabolism , Carnitine O-Palmitoyltransferase/metabolism , Cell Line, Tumor , Citric Acid Cycle/drug effects , Dehydroepiandrosterone/pharmacology , Fatty Acids/metabolism , Glucose/metabolism , Glucosephosphate Dehydrogenase/metabolism , Glutathione/metabolism , Glycolysis/drug effects , Humans , Metabolome/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , NADP/metabolism , Oxidation-Reduction/drug effects , Oxidative Phosphorylation/drug effects , Pentose Phosphate Pathway/drug effects , Pentose Phosphate Pathway/physiology , Pyrazoles/pharmacology , Pyrimidines/pharmacologyABSTRACT
In this study, we established and analyzed a novel human myeloid leukemia cell line, AMU-AML1, from a patient with acute myeloid leukemia with multilineage dysplasia before the initiation of chemotherapy. AMU-AML1 cells were positive for CD13, CD33, CD117, and HLA-DR by flow cytometry analysis and showed a single chromosomal abnormality, 46, XY, t(12;22)(p13;q11.2), by G-banding and spectral karyotyping. Fluorescent in situ hybridization analysis indicated that the chromosomal breakpoint in band 12p13 was in the sequence from the 5' untranslated region to intron 1 of TEL and that the chromosomal breakpoint in band 22q11 was in the 3' untranslated region of MN1. The chimeric transcript and protein of MN1-TEL could not be detected by reverse-transcriptase polymerase chain reaction or Western blot analysis. However, the MN1 gene was amplified to three copies detected by array comparative genomic hybridization analysis, and the expression levels of the MN1 transcript and protein were high in AMU-AML1 cells when compared with other cell lines with t(12;22)(p13;q11-12). Our data showed that AMU-AML1 cells contain t(12;22)(p13;q11.2) without chimeric fusion of MN1 and TEL. The AMU-AML1 cells gained MN1 copies and had high expression levels of MN1. Thus, the AMU-AML1 cell line is useful for studying the biological consequences of t(12;22)(p13;q11.2) lacking chimeric MN1-TEL.
Subject(s)
Cell Line, Tumor , Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 22 , Leukemia, Myeloid/genetics , Oncogene Proteins, Fusion/genetics , Transcription Factors/genetics , Translocation, Genetic , Tumor Suppressor Proteins/genetics , Chromosome Banding , Chromosome Breakpoints , Comparative Genomic Hybridization , Gene Expression , Gene Expression Regulation, Leukemic , Gene Order , Humans , Immunophenotyping , In Situ Hybridization, Fluorescence , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/pathology , Male , Middle Aged , Oncogene Proteins, Fusion/metabolism , Spectral Karyotyping , Trans-Activators , Transcription Factors/metabolism , Transcription, Genetic , Tumor Suppressor Proteins/metabolismABSTRACT
For generation of energy, cancer cells utilize glycolysis more vigorously than oxidative phosphorylation in mitochondria (Warburg effect). We examined the energy metabolism of four leukemia cell lines by using glycolysis inhibitor, 2-deoxy-d-glucose (2-DG) and inhibitor of oxidative phosphorylation, oligomycin. NB4 was relatively sensitive to 2-DG (IC(50): 5.75 mM), consumed more glucose and produced more lactate (waste product of glycolysis) than the three other cell lines. Consequently, NB4 was considered as a "glycolytic" leukemia cell line. Dependency on glycolysis in NB4 was confirmed by the fact that glucose (+) FCS (-) medium showed more growth and survival than glucose (-) FCS (+) medium. Alternatively, THP-1, most resistant to 2-DG (IC(50): 16.14 mM), was most sensitive to oligomycin. Thus, THP-1 was recognized to be dependent on oxidative phosphorylation. In THP-1, glucose (-) FCS (+) medium showed more growth and survival than glucose (+) FCS (-) medium. The dependency of THP-1 on FCS was explained, at least partly, by fatty acid oxidation because inhibitor of fatty acid ß-oxidation, etomoxir, augmented the growth suppression of THP-1 by 2-DG. We also examined the mechanisms by which THP-1 was resistant to, and NB4 was sensitive to 2-DG treatment. In THP-1, AMP kinase (AMPK), which is activated when ATP becomes limiting, was rapidly phosphorylated by 2-DG, and expression of Bcl-2 was augmented, which might result in resistance to 2-DG. On the other hand, AMPK phosphorylation and augmentation of Bcl-2 expression by 2-DG were not observed in NB4, which is 2-DG sensitive. These results will facilitate the future leukemia therapy targeting metabolic pathways.
Subject(s)
Energy Metabolism/physiology , Glycolysis/physiology , Leukemia/metabolism , Oxidative Phosphorylation , Antimetabolites/metabolism , Antimetabolites/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Deoxyglucose/metabolism , Deoxyglucose/pharmacology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/physiology , Energy Metabolism/drug effects , Glucose/metabolism , Glycolysis/drug effects , HL-60 Cells , Humans , Lactic Acid/metabolism , Leukemia/pathology , Oligomycins/pharmacology , Oxidative Phosphorylation/drug effects , Uncoupling Agents/pharmacologyABSTRACT
INTRODUCTION: Thrombosis in myeloproliferative thrombocytosis occurs usually in the microvessels and medium-sized arteries and veins and only rarely in the aorta. Aortic thrombosis is usually treated with thrombectomy. Reported here is a rare case that was treated pharmacologically. CASE PRESENTATION: A 60-year-old Japanese woman presented with numbness of both lower extremities. Her platelet count was 1787 x 103/mul. Through bone marrow examination, we diagnosed her condition as myelodysplastic and/or myeloproliferative disorder-unclassifiable. Abdominal ultrasonography and computed tomographic scan revealed aortic thrombosis. Her platelet count was controlled with hydroxyurea and ranimustine. Aspirin and ticlopidine improved the numbness in both lower limbs on the second day. Aortic thrombosis was not observed in a computed tomographic scan on the seventh day. CONCLUSION: For aortic thrombosis, surgical management is usually adopted, but pharmacological management is also an option because of its immediate curative effects.
ABSTRACT
Endothelial progenitor cells (EPCs) have been isolated from peripheral blood, bone marrow, and umbilical cord blood (CB) and determined to be in heterogeneous populations; however, specific variations in their characteristics remain to be clarified. In this study, we observed that mononuclear cells (MNCs) of CB change in morphology to differentiate into mature endothelial cells (EC) after 6 weeks of culture. In early days of culture along with the differentiation, two distinct populations of EPCs were detected, defined by two-dimensional dot plots (forward scatter vs side scatter) with flow cytometry, namely, relatively small cells (S-EPCs) and relatively large cells (L-EPCs). S-EPCs were found to express CD34 but not CD14, while the converse was the case for L-EPCs. When CD34(+)/CD14(-) cells and CD34(-)/CD14(+) cells were isolated from original MNCs of CB and cultured independently, S-EPCs and L-EPCs were derived from CD34(+)/CD14(-) and from CD34(-)/CD14(+) cells, respectively. Furthermore, when the two EPCs at day 7 were separated by cell sorter and recultured, there was no crossover in terms of CD34 and CD14 expression. While expression of VE-cadherin and vascular endothelial growth factor receptor-2 (VEGFR-2) on L-EPCs was significantly greater than on S-EPCs, levels of CD31 were lower. In addition, L-EPCs exhibited greater proliferative ability on stimulation with VEGF. Although these two EPCs expressed different phenotypes, including growth factor receptors, and had different proliferative ability, they both eventually differentiated into mature ECs after more than 3 weeks of culture.
Subject(s)
Cell Differentiation/physiology , Endothelial Cells/cytology , Fetal Blood/cytology , Stem Cells/classification , Stem Cells/cytology , Antigens, CD34/metabolism , CD13 Antigens/metabolism , Cells, Cultured , Endothelial Cells/classification , Humans , Umbilical Veins/cytologyABSTRACT
Vascular endothelial growth factor (VEGF) and its associated molecule, placenta growth factor (PlGF) are now known to support normal hematopoiesis, and leukemia cell growth. In this study, expression of VEGF and PlGF in acute lymphoblastic leukemia (ALL) cells was examined by real time reverse transcription-polymerase chain reaction in 20 patient samples. Expression of PlGF was more intense in Philadelphia chromosome positive (Ph(+)) ALL than in Ph(-) ALL cases. On the other hand, expression level of VEGF was not different between Ph(+) and Ph(-) cases. Then, PlGF was added to the two ALL cell lines, CRL1929 (Ph(+)), and Nalm6 (Ph(-)). The PlGF stimulated the growth of CRL1929 in time- and dose-dependent manners, although the growth of Nalm6 was not affected by PlGF. The growth stimulation of CRL1929 by PlGF was confirmed by the increase of S phase cells. And the growth promoting effect of PlGF on CRL1929 was cancelled by simultaneous addition of VEGFR1/Fc (which binds to PlGF and abrogates its function), but was not cancelled by VEGFR2/Fc (which does not bind to PlGF). Then, addition of VEGFR1/Fc to the simple culture of CRL1929 demonstrated growth inhibitory effect. These observations demonstrated that PlGF stimulates the growth of Ph(+) ALL cells by both autocrine and paracrine pathways. Finally, PlGF-VEGFR1 loop might be a therapeutic target to improve the prognosis of Ph(+) ALL.
Subject(s)
Autocrine Communication/physiology , Cell Proliferation , Paracrine Communication/physiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Pregnancy Proteins/physiology , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Placenta Growth Factor , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Pregnancy Proteins/genetics , Pregnancy Proteins/pharmacology , RNA, Neoplasm/analysis , Reverse Transcriptase Polymerase Chain Reaction , S Phase , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-1/physiologyABSTRACT
We report an unusual case of angioimmunoblastic T cell lymphoma arising in the setting of 5 years of immunosuppressive treatment for progressive systemic sclerosis. The lymph node lesion was accompanied by large blastic B cells with an association of Epstein-Barr virus. Southern blot study demonstrated the clonal rearrangement of T cell receptor beta-chain gene, but not of immunoglobulin heavy chain gene. Phenotypical examination of the lymph node also revealed the predominance of CD4+ T cells in addition to the proliferation of follicular dendritic cells, but no light chain restriction in large B cell components. In the clinical and laboratory aspects, neutrophilia (15.8 x 10(9)/l) and plasmacytosis (40%) in bone marrow were noted, which were considered to be closely related to elevated serum granulocyte colony-stimulating factor, interleukin (IL)-4 and IL-6. Based on the combined data described here, our preferred diagnosis was angioimmunoblastic T cell lymphoma with Epstein-Barr virus-associated B cell lymphoproliferative disorder, the pathogenesis of which was suggested to be closely associated with immunosuppressive treatment for progressive systemic sclerosis.
Subject(s)
Epstein-Barr Virus Infections/pathology , Herpesvirus 4, Human , Lymphoma, B-Cell/pathology , Lymphoma, T-Cell/pathology , Scleroderma, Diffuse/pathology , Aged , B-Lymphocytes/pathology , B-Lymphocytes/virology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/virology , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Humans , Immunosuppression Therapy/adverse effects , Lymph Nodes/pathology , Lymph Nodes/virology , Lymphoma, B-Cell/complications , Lymphoma, B-Cell/virology , Lymphoma, T-Cell/complications , Lymphoma, T-Cell/virology , Male , Scleroderma, Diffuse/complications , Scleroderma, Diffuse/therapy , T-Lymphocyte Subsets/pathology , T-Lymphocyte Subsets/virologyABSTRACT
Hematopoietic cells and endothelial cells are mutually correlated in their development and growth. Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietins (Angs), are thought to be associated with leukemia cell growth. In this study, we examined if the Angs-Tie2 autocrine pathway works in primary AML cells or not by using soluble Tie2-Fc, which inhibits Angs from binding to Tie2 receptor. After 48 h of culture with Tie2-Fc, nine AML cells from 19 examined samples were not influenced by Tie2-Fc (group A), while AML cells from remaining 10 patients demonstrated remarkable reduction of cell number by Tie2-Fc treatment (group B). Tie2 receptor, upon binding to Angs, are known to activate phosphatidyl-inositol 3 kinase (PI3 kinase). Then, we examined the effect of LY294002, a potent PI3 kinase inhibitor, on primary AML cells. Cell number reduction effect by the treatment of LY294002 was much more prominent in cells of group B than of group A. In addition, extent of cell number reduction by Tie2-Fc and LY294002 was quite well correlated. These observations demonstrated that cells from a part of AML were dependent on autocrine Angs-Tie2 pathway. This notion was further supported by the study of two AML cell lines, KG-1 and HL-60: the growth of KG-1 was suppressed by Tie2-Fc, and also by anti-Tie2 antibody, which inhibits receptor-ligand interaction, while that of HL-60 was not suppressed by Tie2-Fc or anti-Tie2 antibody. Our results will help to explore the angiogenesis-oriented or endothelial cell-mediated therapy for leukemia.
Subject(s)
Angiopoietins/physiology , Leukemia, Myeloid, Acute/blood , Phosphatidylinositol 3-Kinases/metabolism , Receptor, TIE-2/physiology , Angiopoietins/genetics , Bone Marrow/pathology , Cell Line, Tumor , DNA Primers , HL-60 Cells , Humans , Leukemia, Myeloid, Acute/pathology , Receptor, TIE-2/genetics , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, CulturedABSTRACT
We report a case of acute promyelocytic leukemia (APL) with drug-induced hypersensitivity syndrome associated with Epstein-Barr virus (EBV) infection. A 33-year-old woman was admitted because of APL. After complete remission was obtained with the use of all-trans retinoic acid (ATRA), intensive chemotherapy was administered. She developed high grade fever and severe systemic erythematous eruptions followed by cervical lymphoadenopathy, hepatosplenomegaly, hepatitis and hypotension in a state of myelosuppression during consolidation chemotherapy. Systemic corticosteroids alleviated the symptoms. Since an anti-EB VCA IgM antibody titer was continuously positive, persistent infection of EBV was suspected. In this case, EBV infection may have contributed to the development of drug-induced hypersensitivity syndrome.
Subject(s)
Antineoplastic Agents/adverse effects , Drug Hypersensitivity/etiology , Epstein-Barr Virus Infections/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Adrenal Cortex Hormones/therapeutic use , Adult , Antineoplastic Agents/therapeutic use , Antiviral Agents/administration & dosage , Biopsy, Needle , Drug Hypersensitivity/complications , Drug Hypersensitivity/diagnosis , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Female , Follow-Up Studies , Humans , Immunohistochemistry , Leukemia, Promyelocytic, Acute/complications , Leukemia, Promyelocytic, Acute/diagnosis , Risk Assessment , Severity of Illness Index , Treatment OutcomeABSTRACT
We describe a patient who presented with aplastic anaemia associated with the Philadelphia (Ph1) chromosome during immunosuppressive therapy and who subsequently developed myelodysplastic syndrome (MDS) with monosomy 7. Initially the patient had hypocellular fatty marrow without leukaemic blasts or dysplastic features. Chromosome analysis showed 46, XY, t(9;22)(q34;q11) during immunosuppressive therapy, but no leukaemic transformation was detected. The patient showed gradual haematologic improvement and became transfusion independent. Thereafter, bone marrow dysplasia with monosomy 7 progressed following transfusion independence. These findings indicate that multiple cytogenetic evolutions occur in aplastic anaemia during immunosuppressive therapy, and that Ph1 chromosome may play a role in bone marrow suppression rather than development of leukaemia.