ABSTRACT
BACKGROUND: Recent progress in chemotherapy has prolonged the survival of patients with hematological diseases, but has also increased the number of patients with chemotherapy-related cardiac dysfunction (CTRCD). However, the causes of individual variations and risk factors for CTRCD have yet to be fully elucidated.MethodsâandâResults:Consecutive echocardiograms of 371 patients were retrospectively evaluated for the presence of left ventricular (LV) non-compaction (LVNC). Individual LV ejection fraction (LVEF) outcome estimates were made using bivariate linear regression with log-transformed duration Akaike information criterion (AIC) model fitting. The prevalence of LVNC was 6-fold higher in patients with hematological diseases than in those with non-hematological diseases (12% vs. 2%; risk ratio 6.1; 95% confidence interval [CI] 2.0, 18.2). Among patients with hematological diseases, the ratio of myeloid diseases was significantly higher in the group with LVNC (P=0.031). Deterioration of LVEF was more severe in patients with than without LVNC (-14.4 percentage points/year [95% CI -21.0, -7.9] vs. -4.6 percentage points/year [95% CI -6.8, -2.4], respectively), even after multivariate adjustment for baseline LVEF, background disease distributions, cumulative anthracycline dose, and other baseline factors. CONCLUSIONS: LVNC is relatively prevalent in patients with hematological diseases (particularly myeloid diseases) and can be one of the major risk factors for CTRCD. Detailed cardiac evaluations including LVNC are recommended for patients undergoing chemotherapy.
Subject(s)
Heart Diseases , Hematologic Diseases , Ventricular Dysfunction, Left , Heart Diseases/chemically induced , Heart Diseases/epidemiology , Hematologic Diseases/drug therapy , Hematologic Diseases/epidemiology , Humans , Predictive Value of Tests , Prevalence , Retrospective Studies , Ventricular Dysfunction, Left/chemically induced , Ventricular Dysfunction, Left/epidemiology , Ventricular Function, LeftABSTRACT
We recently took advantage of the universal expression of cell adhesion molecule 1 (CADM1) by CD4+ cells infected with HTLV-1 and the downregulation of CD7 expression that corresponds with the oncogenic stage of HTLV-1-infected cells to develop a flow cytometric system using CADM1 versus CD7 plotting of CD4+ cells. We risk-stratified HTLV-1 asymptomatic carriers (AC) and indolent adult T-cell leukemia/lymphoma (ATL) cases based on the CADM1+ percentage, in which HTLV-1-infected clones are efficiently enriched. AC and indolent ATL cases were initially classified according to their CADM1+ cell percentage. Follow-up clinical and flow cytometric data were obtained for 71 cases. In G1 (CADM1+ ≤ 10%) and G2 (10% < CADM1+ ≤ 25%) cases, no apparent clinical disease progression was observed. In G3 (25% < CADM1+ ≤ 50%) cases, five out of nine (55.5%) cases progressed from AC to smoldering-type ATL. In G4 (50% < CADM1+ ) cases, the cumulative incidence of receiving systemic chemotherapy at 3 years was 28.4%. Our results indicate that the percentage of the CD4+ CADM1+ population predicts clinical disease progression: G1 and G2 cases, including AC cases, are stable and considered to be at low risk; G3 cases, including advanced AC cases and smoldering-type ATL cases based on the Shimoyama criteria, are considered to have intermediate risk; and G4 cases, which are mainly indolent ATL cases, are unstable and at high risk of acute transformation.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Carrier State/immunology , Cell Adhesion Molecule-1/analysis , HTLV-I Infections/immunology , Leukemia-Lymphoma, Adult T-Cell/immunology , Adult , Aged , Disease Progression , Female , HTLV-I Infections/drug therapy , Humans , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Male , Middle AgedABSTRACT
We previously reported that the cell adhesion molecule 1 (CADM1) versus CD7 plot in flow cytometry reflects disease progression in human T-cell leukemia virus type 1 (HTLV-1) infection. In CD4(+) cells from peripheral blood, CADM1(-) CD7(+) (P), CADM1(+) CD7(dim) (D) and CADM1(+) CD7(-) (N) subpopulations are observed. The D and N subpopulations increase as asymptomatic HTLV-1 carriers (AC) progress to indolent adult T-cell leukemia-lymphoma (ATL) and the N subpopulation then expands in aggressive ATL. In the present study we examined whether the analysis can estimate the risk of developing ATL in advanced AC. Peripheral blood samples from AC (N = 41) and indolent ATL patients (N = 19) were analyzed by flow cytometry using the CADM1 versus CD7 plot for CD4(+) cells and inverse long PCR (clonality analysis) of FACS-sorted subpopulations. Almost all AC with a high HTLV-1 proviral load (>4 copies/100 cells) had a CADM1(+) (D + N) frequency of >10%. AC with 25% < CADM1(+) ≤ 50% contained expanded clones similar to smoldering-type ATL. In many patients in the 25% < CADM1(+) ≤ 50% group, the proportion of abnormal lymphocytes was distributed around the 5% line, which divides AC and smoldering-type ATL in Shimoyama's classification. In conclusion, the CADM1 versus CD7 plot is useful for selection of putative high-risk AC. The characteristics of some AC and smoldering ATL are said to be similar; however, long-term follow up is required and the clinical outcome (e.g. rate of transformation) of these cases should be used to determine whether to include them in the same clinical category.
Subject(s)
Cell Adhesion Molecules/blood , Flow Cytometry/methods , HTLV-I Infections/pathology , Human T-lymphotropic virus 1/isolation & purification , Immunoglobulins/blood , Leukemia-Lymphoma, Adult T-Cell/pathology , Adult , Aged , Antigens, CD7/blood , Cell Adhesion Molecule-1 , Female , HTLV-I Infections/virology , Human T-lymphotropic virus 1/pathogenicity , Humans , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/virology , Lymphocytes/pathology , Lymphocytes/virology , Male , Middle Aged , Viral LoadABSTRACT
BACKGROUND: The absolute number of adult T-cell leukemia/lymphoma (ATL) cells in peripheral blood is an essential indicator to evaluate disease status. However, microscopically counting ATL cells based on morphology requires experience and tends to be inaccurate due to the rarity of ATL. METHODS: Based on our research showing that acute-type ATL cells are specifically enriched in the CD4+/CD7- (CD7N) fraction, a new analytical method to accurately quantify ATL cells was established using an internal bead standard and simple four-color flow cytometry. This method was verified by comparison with microscopic examination of 49 peripheral blood samples and used to follow up patients. RESULTS: A strong correlation was observed between the number of CD7N cells measured by flow cytometry and the number of abnormal lymphocytes measured microscopically by experienced technicians [Pearson's R, 0.963; Spearman's rho, 0.921; intercorrelation coefficient, 0.962]. The linear regression coefficient was close to 1 (ß=1.013). Our method could detect 1 cell/µL, and the limit of quantitation was between 2.9 and 9.8 cells/µL. The frequency of CD7N cells among CD4+ cells changed during chemotherapy, which reflected differences between chemosensitive and chemoresistant cases. Kaplan-Meier analysis with a log-rank test showed that patients with decreased CD7N proportion after chemotherapy had significantly longer disease-specific survival (p=0.003). CONCLUSIONS: Our newly established method quantified tumor cells in patients with acute-type ATL. Furthermore, this method was useful for assessing the efficacy of chemotherapy, and the change of the CD7N proportion could be more important to predict prognosis.
Subject(s)
Flow Cytometry/methods , Leukemia-Lymphoma, Adult T-Cell/pathology , Adult , Aged , CD4 Antigens/metabolism , Cell Count , Color , Female , Humans , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Leukemia-Lymphoma, Adult T-Cell/metabolism , Male , Middle Aged , Survival Analysis , Treatment OutcomeABSTRACT
Malaria parasites cannot multiply in host erythrocytes without cholesterol because they lack complete sterol biosynthesis systems. This suggests parasitized red blood cells (pRBCs) need to capture host sterols, but its mechanism remains unknown. Here we identified a novel high-density lipoprotein (HDL)-delivery pathway operating in blood-stage Plasmodium. In parasitized mouse plasma, exosomes positive for scavenger receptor CD36 and platelet-specific CD41 increased. These CDs were detected in pRBCs and internal parasites. A low molecular antagonist for scavenger receptors, BLT-1, blocked HDL uptake to pRBCs and suppressed Plasmodium growth in vitro. Furthermore, platelet-derived exosomes were internalized in pRBCs. Thus, we presume CD36 is delivered to malaria parasites from platelets by exosomes, which enables parasites to steal HDL for cholesterol supply. Cholesterol needs to cross three membranes (RBC, parasitophorous vacuole and parasite's plasma membranes) to reach parasite, but our findings can explain the first step of sterol uptake by intracellular parasites.
ABSTRACT
Both adult T-cell leukemia/lymphoma (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can be induced by HTLV-1, but concurrent development has been rarely reported. We present the case of a 55-year-old female who developed cranial nerve symptoms after a 20-year history of HAM/TSP. Although multiple white matter lesions were observed on brain magnetic resonance imaging, no abnormalities were seen on a systemic computed tomography scan. Quantitative flow-cytometric analysis of cell populations in the cerebrospinal fluid (CSF) revealed that most of the infiltrating cells were not inflammatory cells, but HTLV-1-infected CD4+ CADM-1+ T-cells completely lacking CD7 expression. As stepwise downregulation of CD7 is correlated with disease progression from HTLV-1 carrier to aggressive ATL, the CSF cells were classified as aggressive ATL; these cells exhibited a more progressed phenotype than those in peripheral blood (PB). HAM/TSP disease activity was estimated to be low. From these and other examinations, we made a diagnosis of acute-type ATL, which unusually developed in the central nervous system at initial onset prior to systemic progression. In ATL cases with a challenging diagnosis, immunophenotypic characterization of CSF and PB is valuable for differential diagnosis and understanding disease status.
Subject(s)
CD4-Positive T-Lymphocytes/pathology , Cerebrospinal Fluid/cytology , Cerebrospinal Fluid/immunology , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/immunology , Paraparesis, Tropical Spastic/diagnosis , Paraparesis, Tropical Spastic/immunology , Antigens, CD7 , Disease Progression , Fatal Outcome , Female , Flow Cytometry/methods , Human T-lymphotropic virus 1 , Humans , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/virology , Middle Aged , Paraparesis, Tropical Spastic/pathology , Paraparesis, Tropical Spastic/virologySubject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Neoplasm Proteins/biosynthesis , Receptors, CCR4/biosynthesis , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/administration & dosage , Cisplatin/administration & dosage , Clone Cells/metabolism , Cyclophosphamide/administration & dosage , Down-Regulation/drug effects , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Fatal Outcome , Female , Humans , Middle Aged , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Nitrosourea Compounds/administration & dosage , Prednisone/administration & dosage , Receptors, CCR4/genetics , Receptors, CCR4/immunology , Vincristine/administration & dosage , Vindesine/administration & dosageABSTRACT
PURPOSE: Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia-lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development. EXPERIMENTAL DESIGN: We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis. RESULTS: HTLV-I-infected cells were efficiently enriched in CADM1(+) subpopulations (D, CADM1(pos)CD7(dim) and N, CADM1(pos)CD7(neg)). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts. CONCLUSION: The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1(+) cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs.
Subject(s)
Antigens, CD7/biosynthesis , Cell Adhesion Molecules/biosynthesis , HTLV-I Infections/metabolism , Immunoglobulins/biosynthesis , Leukemia-Lymphoma, Adult T-Cell/metabolism , Adult , Biomarkers, Tumor/analysis , Cell Adhesion Molecule-1 , Disease Progression , Down-Regulation , Female , Flow Cytometry , Humans , Leukemia-Lymphoma, Adult T-Cell/pathology , Leukemia-Lymphoma, Adult T-Cell/virology , Male , Oligonucleotide Array Sequence Analysis , Real-Time Polymerase Chain ReactionABSTRACT
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) after a long latency period of about 60 years. As the mature T-cell neoplasms that emerge in patients infected with HTLV-1 are often ATL, T-cell neoplasms developing in such patients tend to be diagnosed simply as ATL without further investigation. However, not all T-cell neoplasms that develop in HTLV-1-infected cases are ATL. Mature T-cell malignancies other than ATL should be carefully excluded in patients infected with HTLV-1, as these sometimes closely resemble ATL in their clinical, morphological, and histological features. Here, we present a case of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) in an HTLV-1 carrier. Confirmation of monoclonal integration of the virus with Southern blotting leads to a definite diagnosis of ATL. Although we did not detect the monoclonal integration band of HTLV-1 in this case, the high HTLV-1 proviral load complicated the diagnosis. Multicolor flow cytometric analysis clearly showed that HTLV-1 was not integrated in the tumor cells, and facilitated discrimination of PTCL-NOS from ATL.
Subject(s)
Carrier State/virology , HTLV-I Infections/virology , Human T-lymphotropic virus 1 , Lymphoma, T-Cell, Peripheral/diagnosis , Lymphoma, T-Cell, Peripheral/etiology , Aged , Female , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , Humans , Immunophenotyping , Lymph Nodes/pathology , Lymphocytes/metabolism , Lymphocytes/pathology , Proviruses , Receptors, Antigen, T-Cell, alpha-beta/genetics , Virus IntegrationABSTRACT
PURPOSE: In a recent study to purify adult T-cell leukemia-lymphoma (ATL) cells from acute-type patients by flow cytometry, three subpopulations were observed in a CD3 versus CD7 plot (H: CD3(high)CD7(high); D: CD3(dim)CD7(dim); L: CD3(dim)CD7(low)). The majority of leukemia cells were enriched in the L subpopulation and the same clone was included in the D and L subpopulations, suggesting clonal evolution. In this study, we analyzed patients with indolent-type ATL and human T-cell leukemia virus type I (HTLV-I) asymptomatic carriers (ACs) to see whether the CD3 versus CD7 profile reflected progression in the properties of HTLV-I-infected cells. EXPERIMENTAL DESIGN: Using peripheral blood mononuclear cells from patient samples, we performed multi-color flow cytometry. Cells that underwent fluorescence-activated cell sorting were subjected to molecular analyses, including inverse long PCR. RESULTS: In the D(%) versus L(%) plot, patient data could largely be categorized into three groups (Group 1: AC; Group 2: smoldering- and chronic-type ATL; and Group 3: acute-type ATL). Some exceptions, however, were noted (e.g., ACs in Group 2). In the follow-up of some patients, clinical disease progression correlated well with the CD3 versus CD7 profile. In clonality analysis, we clearly detected a major clone in the D and L subpopulations in ATL cases and, intriguingly, in some ACs in Group 2. CONCLUSION: We propose that the CD3 versus CD7 plot reflects progression of disease stage in patients infected with HTLV-I. The CD3 versus CD7 profile will be a new indicator, along with high proviral load, for HTLV-I ACs in forecasting disease progression.
Subject(s)
Antigens, CD7/metabolism , CD3 Complex/metabolism , Disease Progression , Flow Cytometry , Human T-lymphotropic virus 1/physiology , Leukemia-Lymphoma, Adult T-Cell/diagnosis , Leukemia-Lymphoma, Adult T-Cell/virology , Adult , Aged , Antigens, CD7/chemistry , Asymptomatic Infections , CD3 Complex/chemistry , Color , Female , Humans , Leukemia-Lymphoma, Adult T-Cell/metabolism , Leukemia-Lymphoma, Adult T-Cell/pathology , Male , Middle Aged , Prognosis , Protein Multimerization , Protein Structure, Quaternary , Risk Factors , Viral LoadABSTRACT
BACKGROUND: Bone morphogenetic protein 4 (BMP4) signaling is involved in the maintenance of hematopoietic stem cells. However, the effects of BMP4 on leukemia and lymphoma cells are unknown. MATERIALS AND METHODS: The effects of recombinant BMP4 on the in vitro growth of 12 leukemia and lymphoma cell lines were examined. RESULTS: BMP4 treatment promoted the short-term growth of three cell lines and suppressed the growth of one. Induction of differentiation was not observed. BMP4 treatment suppressed the clonogenicity of four out of the six examined cell lines. BMP4 treatment promoted the growth of Jurkat cells but suppressed their ability to form colonies. BMP4 treatment up-regulated the phosphorylation of SMAD1/5/8 complex, indicating that BMP4 mediated signal transduction in the cells. CONCLUSION: BMP4 suppressed the clonogenicity of selected leukemia and lymphoma cell lines. The regulation of BMP4 signaling may be a useful therapeutic approach for leukemia and lymphoma, if appropriate cases are selected.
Subject(s)
Bone Morphogenetic Protein 4/pharmacology , Leukemia/drug therapy , Lymphoma/drug therapy , Cell Growth Processes/drug effects , Cell Line, Tumor , Gene Expression/drug effects , Humans , Leukemia/genetics , Leukemia/metabolism , Leukemia/pathology , Lymphoma/genetics , Lymphoma/metabolism , Lymphoma/pathology , Neoplastic Stem Cells/drug effects , Phosphorylation/drug effects , Recombinant Proteins/pharmacology , Smad Proteins/metabolismABSTRACT
The IGH/CCND1 fusion gene has been reported in many hematologic tumors such as mantle cell lymphoma, chronic lymphocytic leukemia, prolymphocytic leukemia, multiple myeloma, and plasma cell leukemia. We report a case of plasma cell leukemia showing five IGH/CCND1 fusion signals by interphase fluorescence in situ hybridization (FISH). Conventional cytogenetic analysis and multicolor spectral karyotyping showed a complex karyotype that did not include t(11;14). Metaphase FISH studies revealed three IGH/CCND1 fusion signals, two of which were amplified signals. These findings indicate that IGH/CCND1 fusion gene was amplified and interspersed in several chromosomes. The patient was treated with intensive chemotherapy. However, the clinical course was very aggressive. The amplification of the IGH/CCND1 fusion gene may contribute to the aggressive course of the disease. To our knowledge, this is the first case showing amplification of the IGH/CCND1 gene in plasma cell neoplasms.