RESUMO
Hematopoietic clones with leukemogenic mutations arise in healthy people as they age, but progression to acute myeloid leukemia (AML) is rare. Recent evidence suggests that the microenvironment may play an important role in modulating human AML population dynamics. To investigate this concept further, we examined the combined and separate effects of an oncogene (c-MYC) and exposure to interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) on the experimental genesis of a human AML in xenografted immunodeficient mice. Initial experiments showed that normal human CD34+ blood cells transduced with a lentiviral MYC vector and then transplanted into immunodeficient mice produced a hierarchically organized, rapidly fatal, and serially transplantable blast population, phenotypically and transcriptionally similar to human AML cells, but only in mice producing IL-3, GM-CSF, and SCF transgenically or in regular mice in which the cells were exposed to IL-3 or GM-CSF delivered using a cotransduction strategy. In their absence, the MYC+ human cells produced a normal repertoire of lymphoid and myeloid progeny in transplanted mice for many months, but, on transfer to secondary mice producing the human cytokines, the MYC+ cells rapidly generated AML. Indistinguishable diseases were also obtained efficiently from both primitive (CD34+CD38-) and late granulocyte-macrophage progenitor (GMP) cells. These findings underscore the critical role that these cytokines can play in activating a malignant state in normally differentiating human hematopoietic cells in which MYC expression has been deregulated. They also introduce a robust experimental model of human leukemogenesis to further elucidate key mechanisms involved and test strategies to suppress them.
Assuntos
Regulação Leucêmica da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-3/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Transplante de NeoplasiasRESUMO
Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of microRNAs (miRNAs) in regulating drug resistance and leukemic stem cell (LSC) fate, we performed global transcriptome profiling in treatment-naive chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor: its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in preclinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185, and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL1 may provide a valuable strategy for overcoming drug resistance in patients.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Quinases Ativadas por p21/genética , Animais , Regulação Leucêmica da Expressão Gênica/genética , Xenoenxertos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Camundongos SCID , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/fisiologia , Quinases Ativadas por p21/metabolismoRESUMO
Aberrantly expressed cytokines in the bone marrow (BM) niche are increasingly recognized as critical mediators of survival and expansion of leukemic stem cells. To identify regulators of primitive chronic myeloid leukemia (CML) cells, we performed a high-content cytokine screen using primary CD34+ CD38low chronic phase CML cells. Out of the 313 unique human cytokines evaluated, 11 were found to expand cell numbers ≥2-fold in a 7-day culture. Focusing on novel positive regulators of primitive CML cells, the myostatin antagonist myostatin propeptide gave the largest increase in cell expansion and was chosen for further studies. Herein, we demonstrate that myostatin propeptide expands primitive CML and normal BM cells, as shown by increased colony-forming capacity. For primary CML samples, retention of CD34-expression was also seen after culture. Furthermore, we show expression of MSTN by CML mesenchymal stromal cells, and that myostatin propeptide has a direct and instant effect on CML cells, independent of myostatin, by demonstrating binding of myostatin propeptide to the cell surface and increased phosphorylation of STAT5 and SMAD2/3. In summary, we identify myostatin propeptide as a novel positive regulator of primitive CML cells and corresponding normal hematopoietic cells.
Assuntos
Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antígenos CD34 , Medula Óssea , Células Cultivadas , Citocinas , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Miostatina/genéticaRESUMO
Plerixafor (P) together with granulocyte colony-stimulating factor (G) is now recognized as an important strategy for mobilizing hematopoietic cells for use in patients given myelosuppressive therapies. However, quantitative comparisons of their ability to mobilize human cells with different hematopoietic activities in vitro or in vivo (in immunodeficient mice) and their interrelationships have not been investigated. To address these questions, we collected samples from 5 normal adult volunteers before and after administering P alone and from another 5 before and after a 4-day course of G and again after a subsequent injection of P. Measurements of their blood content of CD34+ cells, in vitro myeloid colony-forming cells, 3- and 6-week long-term culture (LTC) cell outputs, and levels of circulating human platelets, as well as myeloid and lymphoid cells obtained in immunodeficient mice that received transplants, showed all activities were maximal 4 hours after P preceded by G, and 3-week LTC outputs showed the highest concordance with the 3-week circulating human neutrophil levels obtained in mice that received transplants. Thus, human cells capable of producing neutrophils rapidly in vivo were optimally mobilized by the G + P protocol, and the 3-week LTC assay appears to offer a more specific predictor of their levels than conventional CD34+ cell or colony-forming cell counts.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Animais , Antígenos CD34/sangue , Antígenos CD34/efeitos dos fármacos , Benzilaminas , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Contagem de Células , Técnicas de Cultura de Células , Ciclamos , Xenoenxertos , Humanos , Camundongos , Camundongos SCID , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacosRESUMO
OBJECTIVE: Statins, which are used as cholesterol-lowering agents, have pleiotropic immunomodulatory properties. Although beneficial effects of statins have been reported in autoimmune diseases, the mechanisms of these immunomodulatory effects are still poorly understood. Type I interferons (IFNs) and plasmacytoid dendritic cells (PDCs) represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Therefore, PDCs may be a specific target of statins in therapeutic strategies against SLE. This study was undertaken to investigate the immunomodulatory mechanisms of statins that target the IFN response in PDCs. METHODS: We isolated human blood PDCs by flow cytometry and examined the effects of simvastatin and pitavastatin on PDC activation, IFNalpha production, and intracellular signaling. RESULTS: Statins inhibited IFNalpha production profoundly and tumor necrosis factor alpha production modestly in human PDCs in response to Toll-like receptor ligands. The inhibitory effect on IFNalpha production was reversed by geranylgeranyl pyrophosphate and was mimicked by either geranylgeranyl transferase inhibitor or Rho kinase inhibitor, suggesting that statins exert their inhibitory actions through geranylgeranylated Rho inactivation. Statins inhibited the expression of phosphorylated p38 MAPK and Akt, and the inhibitory effect on the IFN response was through the prevention of nuclear translocation of IFN regulatory factor 7. In addition, statins had an inhibitory effect on both IFNalpha production by PDCs from SLE patients and SLE serum-induced IFNalpha production. CONCLUSION: Our findings suggest a specific role of statins in controlling type I IFN production and a therapeutic potential in IFN-related autoimmune diseases such as SLE.
Assuntos
Células Dendríticas/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Interferon Tipo I/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/enzimologia , Lúpus Eritematoso Sistêmico/imunologiaRESUMO
Patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs) due to a persisting TKI-resistant population of leukemic stem cells (LSCs). From transcriptome profiling, we show integrin-linked kinase (ILK), a key constituent of focal adhesions, is highly expressed in TKI-nonresponsive patient cells and their LSCs. Genetic and pharmacological inhibition of ILK impaired the survival of nonresponder patient cells, sensitizing them to TKIs, even in the presence of protective niche cells. Furthermore, ILK inhibition eliminated TKI-refractory LSCs from patients, but not normal HSCs, in vitro and in vivo. RNA-sequencing and functional validation studies implicated an important role of ILK in maintaining a requisite level of mitochondrial oxidative metabolism in highly purified, quiescent LSCs. Thus, these findings point to ILK as a critical survival mediator to TKIs and quiescent stem cells, offering an attractive therapeutic target and model for curative combination therapies in stem-cell-driven cancers.
Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Células-Tronco Neoplásicas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina QuinasesRESUMO
ABCG2 is a transporter preferentially expressed in a primitive subpopulation of cells and recently reported as a surviving factor for trophoblasts. To date, manner of ABCG2 expression in lymphoid tissues is not known. Immunohistochemically, strong ABCG2 expression was found in a small proportion of plasma cells mainly located in the interfollicular space of lymphoid tissues. The number of ABCG2-high plasma cells increased in interleukin-6- (IL-6) rich lesions, such as Castleman's disease of plasma cell type. Plasma cells are subjected to endoplasmic reticulum (ER) stress when excess proteins are synthesized, and IL-6 stimulates protein synthesis. Therefore, the effect of IL-6 and ER stress on ABCG2 expression in plasma cells was examined. The expression level of ABCG2 increased by treatment with either IL-6 or ER stress inducers, and further increased with both. The promoter analysis revealed that the effect of IL-6 and ER stress inducers was mediated through the site overlapping XBP-1 and HIF-1 binding sequences. Knocked-down of ABCG2 by siRNA or ABCG2 inhibitor reduced plasma cell viability under ER stress. These suggest that ABCG2 is a surviving factor for plasma cells. To our knowledge, this is the first study reporting the effect of ER stress on ABCG2 expression.
Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Retículo Endoplasmático/metabolismo , Interleucina-6/metabolismo , Proteínas de Neoplasias/metabolismo , Plasmócitos/metabolismo , Estresse Fisiológico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular , Metilação de DNA/efeitos dos fármacos , Expressão Gênica , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma/metabolismo , Proteínas de Neoplasias/genética , Tonsila Palatina/metabolismo , Tonsila Palatina/patologia , Regiões Promotoras Genéticas , Tapsigargina/farmacologia , Tunicamicina/farmacologiaRESUMO
PURPOSE: Our recent study revealed that CD55-high population in breast cancer cell line was resistant to apoptosis and formed colonies in vitro more efficiently than CD55-low population. The present study was conducted to examine whether CD55-high population in breast cancer cell line possesses higher tumorigenic potential in vivo and presence of CD55-high cells in breast cancer affects clinicopathologic behavior of patients. EXPERIMENTAL DESIGN: CD55-high and CD55-low population was sorted from breast cancer cell line, injected into immunodeficient mice, and the resultant tumor volume was measured. CD55 expression was immunohistochemically examined in clinical samples from 74 cases with breast cancers, and cases with >1% of tumor cells showing high level of CD55 expression were categorized as CD55 high. RESULTS: The xenotransplanted tumor volume derived from CD55-high population was significantly larger than that from CD55-low population. Fifty (67.6%) of 74 cases of breast cancer were CD55-high. A significant correlation was observed between CD55-high character and relapse rate (P < 0.001). Univariate analysis showed that tumor size (P = 0.005) and CD55 expression (P = 0.005) were unfavorable prognostic factors. Multivariate analysis revealed that the tumor size (P = 0.013) and CD55 expression (P = 0.011) were independent prognostic factors. CONCLUSIONS: CD55 play an important role in tumorigenesis of breast cancer, and presence of small population of cells with strong CD55 expression would be sufficient to predict poor prognosis of patients.
Assuntos
Neoplasias da Mama/metabolismo , Antígenos CD55/biossíntese , Regulação Neoplásica da Expressão Gênica , Neoplasias Mamárias Animais/metabolismo , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Transplante de Neoplasias , Prognóstico , Fatores de TempoRESUMO
Human B-cell precursor acute lymphoid leukemias (BCP-ALLs) comprise a group of genetically and clinically distinct disease entities with features of differentiation arrest at known stages of normal B-lineage differentiation. We previously showed that BCP-ALL cells display unique and clonally heritable, stable DNA replication timing (RT) programs (ie, programs describing the variable order of replication and subnuclear 3D architecture of megabase-scale chromosomal units of DNA in different cell types). To determine the extent to which BCP-ALL RT programs mirror or deviate from specific stages of normal human B-cell differentiation, we transplanted immunodeficient mice with quiescent normal human CD34+ cord blood cells and obtained RT signatures of the regenerating B-lineage populations. We then compared these with RT signatures for leukemic cells from a large cohort of BCP-ALL patients with varied genetic subtypes and outcomes. The results identify BCP-ALL subtype-specific features that resemble specific stages of B-cell differentiation and features that seem to be associated with relapse. These results suggest that the genesis of BCP-ALL involves alterations in RT that reflect biologically significant and potentially clinically relevant leukemia-specific epigenetic changes.
Assuntos
Cromossomos/genética , Período de Replicação do DNA , Leucemia/genética , Leucemia/patologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores , Neoplasias do Sistema Nervoso Central/secundário , Biologia Computacional/métodos , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Variação Genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Xenoenxertos , Humanos , Imunofenotipagem , Leucemia/mortalidade , Masculino , Camundongos , Camundongos Knockout , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologiaRESUMO
The majority of cases of intravascular lymphomatosis (IVL) is derived from B cells. However, IVL may also arise from T cells, or more rarely NK cells. The clinicopathological findings in six cases of NK-cell IVL (NK-IVL), including one new case, were summarised and compared with B-cell IVL (B-IVL) and T-cell IVL (T-IVL). Earlier onset of disease and female predominance were found in NK-IVL. NK-IVL was typically Epstein-Barr virus (EBV)-positive, whereas EBV was rarely detected in B-IVL. Cutaneous manifestations were common in NK-IVL with constant EBV infection. B-IVL showed a more favourable prognosis than T- or NK-IVL. Irrespective of immunophenotype, however, IVL showed a less favourable prognosis than ordinary lymphomas within the same immunophenotype. In summary, IVL of the B-, T- and NK-cell phenotypes is clinicopathologically distinct and shows similarities to their more common counterparts, i.e. diffuse large B-cell lymphoma, peripheral T-cell lymphoma, unspecified and extranodal NK/T-cell lymphoma, nasal type.
Assuntos
Células Matadoras Naturais/patologia , Linfoma não Hodgkin/patologia , Neoplasias Vasculares/patologia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Humanos , Linfoma de Células B , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/virologia , Linfoma de Células T , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Neoplasias Vasculares/tratamento farmacológico , Neoplasias Vasculares/virologiaRESUMO
A 69-year-old man was admitted to our hospital with fever and right neck lymphadenopathy. A neck lymph node biopsy was performed. In the specimens, immunoblasts were present with an admixture of small T lymphocytes and macrophagocytes. Immunohistochemcal staining of immunoblasts was positive for CD20, CD30 and EBER. Epstein-Barr virus (EBV) serology showed elevated IgG antibody to VCA, and EBV DNA was detected in the peripheral blood. Since he showed latency II without immunodeficiency disease, we diagnosed age-related EBV-associated B-cell lymphoproliferative disorder (EBV-LPD) as a result of aging and EBV infection. He was treated with 6 courses of the CHOP regimen plus rituximab, and achieved complete remission. EBV-DNA became undetectable at remission. In age-related EBV-LPD, there is some possibility that EBV-DNA in the peripheral blood is valuable as a tumor biomarker.
Assuntos
DNA Viral/sangue , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Transtornos Linfoproliferativos/virologia , Idoso , Envelhecimento , Linfócitos B , Humanos , MasculinoRESUMO
Genome-wide DNA replication timing (RT) profiles reflect the global three-dimensional chromosome architecture of cells. They also provide a comprehensive and unique megabase-scale picture of cellular epigenetic state. Thus, normal differentiation involves reproducible changes in RT, and transformation generally perturbs these, although the potential effects of altered RT on the properties of transformed cells remain largely unknown. A major challenge to interrogating these issues in human acute lymphoid leukemia (ALL) is the low proliferative activity of most of the cells, which may be further reduced in cryopreserved samples and difficult to overcome in vitro. In contrast, the ability of many human ALL cell populations to expand when transplanted into highly immunodeficient mice is well documented. To examine the stability of DNA RT profiles of serially passaged xenografts of primary human B- and T-ALL cells, we first devised a method that circumvents the need for bromodeoxyuridine incorporation to distinguish early versus late S-phase cells. Using this and more standard protocols, we found consistently strong retention in xenografts of the original patient-specific RT features. Moreover, in a case in which genomic analyses indicated changing subclonal dynamics in serial passages, the RT profiles tracked concordantly. These results indicate that DNA RT is a relatively stable feature of human ALLs propagated in immunodeficient mice. In addition, they suggest the power of this approach for future interrogation of the origin and consequences of altered DNA RT in ALL.
Assuntos
Proliferação de Células , Replicação do DNA , DNA de Neoplasias/biossíntese , Transplante de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Animais , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologiaRESUMO
Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect posttransplantation reconstitution dynamics remain poorly understood. Here, we show that an equivalent level of human chimerism can be regenerated from human CD34+ cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2- to 6-month-old NOD-Rag1-/--IL2Rγc-/- (NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient NOD-Prkdcscid/scid-IL2Rγc-/- (NSG) hosts. Comparison of sublethally irradiated and non-irradiated NRG mice and W41/W41 derivatives showed superior chimerism in the W41-deficient recipients, with some differential effects on different lineage outputs. Consistently superior outputs were observed in female recipients regardless of their genotype, age, or pretransplantation conditioning, with greater differences apparent later after transplantation. These results define key parameters for optimizing the sensitivity and minimizing the intraexperimental variability of human hematopoietic xenografts generated in increasingly supportive immunodeficient host mice.
Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Fatores Etários , Animais , Biomarcadores , Contagem de Células , Feminino , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunofenotipagem , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Fatores Sexuais , Quimeras de Transplante , Transplante HeterólogoRESUMO
An adult patient suffering from G-CSF-resistant very severe aplastic anemia received a cord blood transplantation from a three-loci HLA-mismatched unrelated donor after nonmyeloablative conditioning. Cord blood was infused after conditioning with fludarabine (180 mg/m2) and cyclophosphamide (100 mg/kg). Cyclosporin A and short-term methotrexate were used for prophylaxis against acute GVHD. Engraftment was achieved on day 23, and there was no serious GVHD. A full-donor type T-cell chimerism was obtained by day 30. Normal hematopoiesis and complete chimerism have been maintained 14 months after transplantation.
Assuntos
Anemia Aplástica/terapia , Sangue Fetal/transplante , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Adulto , Anemia Aplástica/imunologia , Feminino , Humanos , Condicionamento Pré-TransplanteRESUMO
Plasma cell leukemia (PCL) is a rare disease that represents approximately 4% of plasma cell malignant disorders. PCL consists of two variants: primary PCL presents in patients with no previous history of multiple myeloma, while secondary PCL consists of a leukemic transformation in a previously recognized multiple myeloma. Primary PCL is an extremely resistant, rapidly progressive, fatal disease, with a median overall survival of 6.8 months. There is no standard therapeutic strategy, because no treatment option has been prospectively evaluated. We describe a successful case of newly diagnosed primary PCL, treated with a regimen that included bortezomib, followed by auto stem cell transplantation and nonmyeloablative allogeneic stem cell transplantation. Our patient has maintained remission status for over 12 months since undergoing the allogeneic stem cell transplantation. This strategy is promising for PCL, which, though an extremely resistant disease, may become curable.
RESUMO
Some thrombopoietin receptor-agonists (TPR-As) have been developed and shown to be highly effective in the treatment of immune thrombocytopenic purpura (ITP). Soluble cytotoxic T-lymphocyte-associated antigen 4 (sCTLA-4) can modulate and terminate the immune response. Several reports have shown that sCTLA-4 levels are elevated in patients with some autoimmune disorders. However, sCTLA-4 levels have not previously been investigated in TPR-A exposed patients with ITP. We investigated the levels of transforming growth factor (TGF) ß(1) and sCTLA-4 in ITP patients to determine the clinical association with TGFß(1) and sCTLA-4 in TPR-A-exposed patients with ITP. Thirty-seven ITP patients were divided into 2 groups (TPR-A-exposed: 13 patients; unexposed: 24 patients). Doses of eltrombopag ranging from 12.5mg to 50mg were administered daily, and biochemical data obtained before and after eltrombopag administration were compared. Eltrombopag therapy significantly increased sCTLA-4 and TGFß(1) levels relative to baseline in patients with ITP. In addition, plasma TGFß(1) was positively correlated with platelet counts and sCTLA-4 in patients with ITP in the eltrombopag-exposed group. However, no significant change in the detection rate for anti-glycoprotein antibody was observed before and 24 weeks after eltrombopag treatment. These results suggest that eltrombopag can partially modulate some immune responses by TGFß(1) and sCTLA-4, but it does not induce immune tolerance by 24 weeks after treatment.
Assuntos
Benzoatos/administração & dosagem , Antígeno CTLA-4/sangue , Hidrazinas/administração & dosagem , Púrpura Trombocitopênica/tratamento farmacológico , Púrpura Trombocitopênica/imunologia , Pirazóis/administração & dosagem , Receptores de Trombopoetina/agonistas , Fator de Crescimento Transformador beta1/sangue , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica/sangue , Resultado do TratamentoRESUMO
Thrombotic thrombocytopenic purpura (TTP) is a multisystemic microvascular disorder that may be caused by an imbalance between unusually large von Willebrand factor multimers and the cleaving protease ADAMTS13. In acquired TTP, especially in secondary TTP with various underlying diseases, the diagnosis is difficult because there are many cases that do not exhibit severe deficiency of ADAMTS13 or raised levels of ADAMST13 inhibitors. It is well known that collagen disease, malignancy, and hematopoietic stem cell transplantation can be underlying conditions that induce TTP. However, TTP induced by acute pancreatitis, as experienced by our patient, has rarely been reported. Our patient completely recovered with treatments using steroids and plasma exchange (PE) only. In cases where patients develop acute pancreatitis with no apparent causes for hemolytic anemia and thrombocytopenia, the possibility of TTP should be considered. Treatments for TTP including PE should be evaluated as soon as a diagnosis is made.
RESUMO
We report a case of acute mixed-lineage leukemia, as seen in a 65 year-old female with MLL gene amplification and biallelic loss of wild type p53 gene. The diagnosis was based on the findings that her bone marrow (BM) blasts expressed cytoplasmic CD3 (cyCD3), B-lineage antigens and myeloid antigens accompanied by clonal rearrangements of IgH gene. The BM blasts consisted of small-sized peroxidase-negative blasts (97%) and large-sized peroxidase-positive blasts (3%). The BM blasts showed a complex "karyotype," including dic(17;20) (p11;q11), -5 and add (11q23). Add (11q23) abnormality was found in sideline karyotypes as well as the stemline abnormality of dic(17;20) (p11;q11). For the p53 gene, which is located at 17p13, fluorescence in situ hybridization analysis showed the loss of one of two p53 alleles. Furthermore, polymerase chain reaction-single-strand conformation polymorphism and following nucleotide sequencing showed that the p53 gene was mutated at codon 215, leading to an amino acid substitution from Ser to Arg. For the MLL gene, southern blot analysis showed that the MLL gene locus was amplified but not rearranged at its breakpoint cluster region, which is usually rearranged in balanced translocations with many partner genes. These findings suggest that MLL gene amplification may in this case be based on the genetic instability caused by the preceding biallelic loss of the wild type p53 gene.
Assuntos
Amplificação de Genes , Leucemia Aguda Bifenotípica/genética , Translocação Genética , Medula Óssea , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 17 , Feminino , Genes p53 , Humanos , Hibridização in Situ FluorescenteRESUMO
Lymphoproliferative disorder (LPD) with polymorphous composition of proliferation (polymorphous LPD), containing large lymphoid cells together with small lymphocytes, plasma cells, macrophages, and/or eosinophils, is found in individuals with immunodeficiency conditions. Clinicopathological findings in 19 cases of polymorphous LPD registered with the Osaka Lymphoma Study Group, Osaka, Japan, were analyzed; they represented 0.4% of the registered cases. In six cases, there was a history of rheumatoid arthritis; five of them had received immunosuppressive agents. There were no acquired immunodeficiency syndrome cases or organ transplant recipients. Southern blotting and/or polymerase chain reaction (PCR)-based clonality analysis revealed monoclonal B cell and T cell proliferation in eight and six cases (B- and T-LPD), respectively, and polyclonality in one. In B-LPD, there was polymorphous proliferation, containing large B-lymphoid cells, while medium-to-large T lymphoid cells with occasional eosinophilic infiltration were seen in T-LPD. Epstein-Barr virus (EBV) was detected in three of eight B-LPD, four of six T-LPD, and one of one polyclonal LPD. The prognosis was not favorable; the 3-year overall survival rate was 49.7 +/- 17.3%. Thus, polymorphous LPD is relatively rare in Japan and is a heterogeneous disease with monoclonal proliferation of B or T cells; additionally, it is occasionally EBV-associated, and behaves as an aggressive lymphoma.
Assuntos
Síndromes de Imunodeficiência/patologia , Linfoma/patologia , Transtornos Linfoproliferativos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Células Clonais/patologia , Infecções por Vírus Epstein-Barr/patologia , Feminino , Herpesvirus Humano 4/isolamento & purificação , Humanos , Japão/epidemiologia , Linfoma/epidemiologia , Linfoma/virologia , Transtornos Linfoproliferativos/epidemiologia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Linfócitos T/patologiaRESUMO
A 60-year-old woman with Sjögren's syndrome showed recurrence of parotid mucosa-associated lymphoid tissue (MALT) lymphoma with a simultaneous increase of serum sIL-2R antigen levels 10 years after surgical treatment. Helicobacter pylori infection had been detected in the stomach since the beginning of the lymphoma. Although H. pylori was not detected in the recurrent parotid lymphoma, antibiotic therapy contributed not only to successful eradication of gastric H. pylori but also to disappearance of the recurrent lymphoma. Further studies on the mechanisms of occurrence of extragastric MALT lymphomas are needed to establish the treatment of extragastric MALT lymphomas.