Reaserch Advances on the Role of PI3K/AKT Signaling Pathway and MiRNA in Acute T-Cell Lymphocytic Leukemia--Review / 中国实验血液学杂志

Abstract　　Numerous studies have confirmed that abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is one of the most common induction mechanisms of T-ALL. In recent years, many literature report that multiple abnormally expressed microRNAs (miRNAs) can participate in the development of T-ALL by regulating the PI3K/AKT signaling pathway. For example, overexpression of miR-19 and miR181a can activate the PI3K/AKT signaling pathway, which leads to the development of T-ALL and induction of chemotherapy drug resistance, as well as the low expression of miR-26b and miR-29a. Apart from the inhibitors and traditional Chinese medicines that target the PI3K/AKT signaling pathway, regulation of the expression of the corresponding miRNA may also be a potential treatment protocol for T-ALL. The mechanisms of PI3K/AKT signaling pathway involved in the development of T-ALL, the role of miRNAs in the PI3K/AKT signaling pathway and the targeted therapy based on this signaling pathway are summarized briefly in this review.

Sobrevida global de pacientes con leucemia aguda en el Hospital de Especialidades Pediátricas de Chiapas, México / Childhood acute leukemia overall survival at the Hospital de Especialidades Pediátricas in Chiapas, México

Resumen: Introducción: A 10 años de la fundación del Hospital de Especialidades Pediátricas en Chiapas, México, es importante valorar la sobrevida global a 5 años de los pacientes con leucemia aguda bajo el régimen del Seguro Popular. Métodos: Estudio descriptivo y de sobrevida de 210 casos de leucemia aguda diagnosticados y tratados entre 2008 y 2012. Empleando curvas de Kaplan-Meier se analizó cada variedad de la enfermedad (B, T y mieloide), y para la leucemia B en función del grupo de riesgo, el sexo, la edad, los leucocitos al diagnóstico, los marcadores de superficie, el índice de DNA, el cariotipo y las translocaciones. Resultados: La edad, el sexo y la proporción de tipos de leucemia aguda (B = 85%; M = 10%; T = 5%) fueron similares al resto del país. El 20% de los pacientes estaban vivos a 5 años; el 53% habían fallecido y el 27% abandonaron el tratamiento. La sobrevida global a 5 años fue del 42% (B = 45%; T = 20%; M = 10%) (mediana: 38.8 meses; intervalo de confianza del 95%: 28.9-48.7). La mediana de «muy alto riesgo¼ fue de 7.7 contra 47 meses; no hubo diferencia entre riesgo habitual y alto riesgo. Los leucocitos < 50,000/µl al diagnóstico y CD10 positivo se asociaron con mejor sobrevida. En el momento del deceso, el 29% se encontraba en remisión. Conclusiones: La sobrevida de la leucemia aguda bajo el Seguro Popular fue desfavorable los primeros 5 años del Hospital de Especialidades Pediátricas. Se identificaron como contribuyentes la alta tasa de mortalidad temprana, de pacientes en remisión y el abandono. Además de revisar la atención médica, se requiere el estudio de elementos extrahospitalarios determinantes del abandono para mejorar el programa.

Abstract: Background: At the 10th anniversary of the Hospital de Especialidades Pediátricas in Chiapas, Mexico, it was important to assess the 5-year acute leukemia overall survival under the Seguro Popular program (Popular Insurance). Methods: A descriptive and survival study of 210 acute leukemia patients diagnosed and treated during 2008-2012 was performed. Kaplan-Meier survival curves were developed for all patients, each leukemia type (B, T and myeloid) and for B type related to risk group, age, sex, leukocytes, cell markers, DNA index, karyotype, and translocations. Results: Age, gender and proportion of leukemia types (B = 85%; M = 10%; T = 5%), were similar to other parts of the country. At the end of the 5-year treatment, 20% of the patients were alive, 53% had died and 27% had abandoned the treatment. Global survival was 42% (B = 45%; T = 20%; M = 10%) (median: 38.8 months; confidence interval of 95% = 28.9-48.7). Very high-risk median survival was 7.7 versus 47 months. There was no difference between standard and high-risk groups. The initial leukocyte count < 50,000/µL and CD10 positive were related to better B survival; no other variables were related. At the time of death, 29% of patients were in remission. Conclusions: Global survival of acute leukemia at Hospital de Especialidades Pediátricas under the Seguro Popular during its first 5 years was surprisingly poor given the medical resources available through the insurance. Early mortality, death during remission and high desertion rates contributed to these results. A detailed revision of treatment protocols and reasons for abandoning treatment is mandatory.

Protothecosis in a patient with T cell lymphocytic leukemia / Prototecosis en un paciente con leucemia linfocítica de células T

Human protothecosis is a rare infection caused by algae of the genus Prototheca. Prototheca wickerhamii has been recognized as the main species that causes infection in immunocompromised hosts with deficits in innate or cellular immunity. We report a case of persisting subcutaneous protothecosis in a patient with T-cell large granular lymphocyte leukemia, who also presented a history of disseminated histoplasmosis.

La prototecosis humana es una infección rara causada por algas del género Prototheca. Prototheca wickerhamii ha sido reconocida como la principal especie causante de infección en huéspedes inmunocomprometidos, con déficit de inmunidad innata o celular. Presentamos un caso de prototecosis subcutánea persistente en un paciente con leucemia linfocítica granular de células T, con antecedentes de histoplasmosis diseminada.

HTLV-1 bZIP Factor (HBZ): Roles in HTLV-1 Oncogenesis / 病毒学报

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus demonstrated to be associated with human disease. Infection by the HTLV-1 can cause T-cell leukemia (ATL) in adults. HTLV-1 bZIP factor (HBZ) is a viral protein encoded by the minus strand of the HTLV-1 provirus. Among the regulatory and accessory genes of HTLV-1, HBZ is the only gene that remains intact and which is expressed consistently in all patients with ATL. Moreover, HBZ has a critical role in the leukemogenesis of ATL. Here, we review the function of HBZ in the oncogenesis of HTLV-1 and its molecular mechanism of action.

Effect of Emodin Derivative E11 on T Lymphocytic Leukemia Cell Line Molt-4 and Its Possible Mechanisms / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To explore the effect of a new emodin derivative E11 on proliferation and apoptosis of T lymphocytic leukemia cell line Molt-4 and its possible mechanisms.</p><p><b>METHODS</b>MTT method was used to plot cell growth curve. Colony culture assay was performed for studying the effect of emodin derivative E11 on colony-formation of Molt-4. The fluorescent microscopy with DAPI staining was used to examine the cell morphological changes after E11 treatment. DNA fragmentation method was used to detect the inducing effect of emodin derivative E11 on cell apoptosis. Western blot was used to determine the expressions of apoptosis-related proteins including procaspase-9, procaspase-3, PARP and PI3K/AKT, MAPK signalling pathway.</p><p><b>RESULTS</b>Emodin derivative E11 could strongly inhibit the growth of Molt-4 with the IC50 in 48 h at 1.381 ± 0.1552 µmol/L in dose-dependent manner. 0.1 µmol/L of E11 could inhibit cell colony formation. The typrical apopototic morphologic changes of Molt cells treated with E11 could be observed under fluorescence microscope with DAPI staining. DNA apoptotic ladder could be observed by DNA fragmentation.The expressions of procaspase -9, procaspase-3, PARP, p-MAPK, p-AKT, mTOR, p-mTOR, p-P70 and p-4BEP1 were down-regulated, while expressions of MAPK, AKT, 4EBP1 and P70 were not changed remarkably after Molt-4 were treated with E11 for 48 h.</p><p><b>CONCLUSION</b>E11 can remarkably inhibit the proliferation and induce the apoptosis of Molt-4 cells. The mechanism of apoptosis of Molt-4 cells may be related with the suppression of PI3K/AKT and MAPK signalling pathways.</p>

A Case of Progressive Outer Retinal Necrosis Treated by Combined Intravitreal Foscarnet and Ganciclovir

PURPOSE: To report a case of progressive outer retinal necrosis treated by combined intravitreal foscarnet and ganciclovir. CASE SUMMARY: A 11-year-old male with a history of chemotherapy and cord blood transplantation due to precursor T-cell leukemia developed Herpes zoster lesion on his forehead and rapidly progressing peripheral retinal necrosis without vasculitis in the right eye. Varicella-Zoster virus was confirmed in his cerebrospinal fluid using polymerase chain reaction (PCR); and the patient was diagnosed with progressive outer retinal necrosis. Despite combined treatment with intravenous acyclovir and foscarnet and intravitreal foscarnet, retinal necrosis progressed to retinal detachment and total retinal necrosis. During follow-up, new retinal necrosis was observed in his left eye. The patient was started on combined intravenous and intravitreal foscarnet and ganciclovir; retinal necrosis in the left eye regressed and posterior pole was spared. With subsequent oral valganciclovir and intravitreal foscarnet and ganciclovir, the remaining retina was preserved with maintained vision.

Evaluación de la actividad antiproliferativa y proapoptótica de compuestos kauranos sobre líneas celulares de leucemia humana / Evaluation of the antiproliferative and proapoptotic activity of kauran compounds on human leukemia cell lines

En Venezuela y el mundo, el cáncer es la segunda causa de morbi-mortalidad, y la leucemia es uno de los tipos de cáncer que afecta a nuestra población. La principal características de las celulas linfoides y mieloides presentes en la leucemia es que son pocos funcionales y además no responden a las señales proapoptóticas. Por lo tanto, en la búsqueda de compuestos de mejor perfil terapéutico, se evaluó el efecto de compuestos de tipo seco ent-kauranos aislados de plantas terrestres en las lineas celulares jurka E6.1 y HL60 sobre el crecimiento celular a través del método colorimétrico del MTT, la inducción de apoptosis a través del uso de la microscopia confocal, la citometría de flujo y los micro arreglos de proteínas; y sobre el ciclo celular, la actividad de la vía del NFkB y la diferenciación celular también a través de la citometría de flujo. Se determino que el ácido de casacasina, y la caracasina, disminuyeron la proliferación cecular, indujeron el arresto del ciclo celular, provocaron la externalización de la fosfatidilserina y la activación de las capasas 3, 7, 8 y 9, a la vez que promovieron la disminución del potencial mitocondrial, incrementaron la expresión de las proteínas proapoptóticas en ambas líneas celulares, disminuyeron la activación de la vía de señalización del NFkB en la línea celular Jurkat E6.1, y ademas indujeron la expresión de la proteína CD40 e incrementaron la producción de especies reactivas de oxigeno en la línea celular HL60, por lo que estos compuestos ent-kauranos poseen un alto potencial anticancerígeno para la leucemia linfocítica aguda de células T y para la leucemia promielocítica

Células epiteliais do timo são possível reservatório viral e transmitem o HTLV-1 para linfócitos T CD4 / Thymic epithelial cells are infected by htlv-1 and transmit the virus to cd4 t lymphocytes

O timo é um órgão linfoide primário, sítio do desenvolvimento de células T, provendofatores críticos e coordenados que induzem e suportam o comprometimento delinhagem, diferenciação e sobrevivência dessas células. A presença das célulasnão-linfóides, principalmente as células epiteliais do timo (TEC) no parênquimatímico promove a migração e diferenciação coordenada dos linfócitos T. Os linfócitosT são o principal alvo do Virus linfotrópico T humano (HTLV-1), agente etiológico daleucemia/linfoma associado ao HTLV-1 (ATL) e de doença que compromete osistema nervoso/muscular (HAM/TSP). É desconhecida a causa que leva a uma ououtra doença. A resposta imune antiviral mediada por células T é ineficiente nessaspatologias. Mesmo que o vírus tenha tropismo pelos linfócitos T, ele é capaz deinfectar outros tipos celulares por contato direto entre células ou por partículas viraislivres. Linfócitos ativados recirculam pelos órgãos linfoides, incluindo o timo, onde ascélulas epiteliais tímicas (TEC) interagem intimamente com as células recirculantes,promovendo uma possível via de transmição do HTLV-1. No nosso trabalho,observamos que as TECs possuem os receptores para a entrada do vírus (GLUT-1e Neuropilina-1). Experimentos in vitro mostraram que as TECs podem serinfectadas pelo HTLV-1 por linhagens de linfócitos derivados de pacientesportadores de ATL e de HAM/TSP. Essas infecções ocorreram tanto por contatodireto entre as células, quanto por sobrenadante contendo partículas virais livresderivadas do sobrenadante dos linfócitos. O vírus pode ser observado após 24horas e 10 dias de cultivo, quando a maioria das células estava infectada. Atravésde microscopia eletrônica de transmissão, foram observadas partículas viraisbrotando de estruturas semelhantes a corpos multivesculares nas TECs...

The thymus is a primary lymphoid organ, site of developing T cells, providing acoordinated set of critical factors to induce and support lineage commitment,differentiation and survival of these cells. The presence of non-lymphoid cellsthrough the thymic parenchyma serves to provide coordinated migration anddifferentiation of T lymphocytes. T lymphocytes are the main target of Human TLymphotropic Virus type 1 (HTLV-1). This virus is the etiologic agent of HTLV-1associated lymphoma and leukemia (ATL) or a disease of muscular/nervous systems(HAM/TSP), but it is unknown what triggers to one or other disease. T-cell mediatedimmune response against viral proteins is not effective in both diseases. Althoughthe virus has T lymphocyte tropism, it can infect other cells by cell contact and cellfreevirus. Activated T lymphocytes circulates around lymphoid organs, including thethymus, where the thymic epithelial cells (TEC) strongly interact with recirculatingcells, so infected lymphocytes could transmit the virus to TEC. Interestingly, in ourwork we observed that TEC expresses molecules related to the HTLV-1 transmission(GLUT-1, Neuropilin 1). In vitro experiments showed that TEC could be infected bycell lineages derived from ATL and HAM/TSP patients. These infections happenedfrom cell contact and by cell-free virus derived from cell supernatants. The virus canbe seen after 24h and after 10 days, when most cells in the culture were infected. Bytransmission electron microscopy, virus particles were observed budding frommultivesicular bodies like structures in TEC. Cytokines and chemokines wereincreased at mRNA level soon after contact with HTLV-1 containing supernatantderived from lymphocytes. In addition, type 1 interferon and interferon stimulatedgenes were decreased in HTLV-1 infected TEC...

Case report of adult T-cell lymphoma/leukemia / Relato de caso de linfoma/leucemia de células T do adulto

The adult T-cell leukemia/lymphoma (ATLL) is a rare type of lymphoma caused by human T lymphotropic virus type 1 (HTLV-1). The clinical manifestations include cutaneous lesions, adenopathies, myelopathy/ tropical spastic paraparesis, uveitis, ophthalmological diseases, leukocytosis with lymphocytosis and atypical lymphocytes. The main objective of this study was to report a case of a female patient with ATLL, a farmer with leukocytosis, lymphocytosis, bilateral ocular erythema, cervical lymphadenopathy, in the abdominal visceromegalies and with positive markers for T-cell lymphocytes (CD45, CD2, CD3, CD5, CD4 and CD25). Although ATLL is a rare disease, its delayed diagnosis may lead to serious complications and fatal outcome.

O linfoma/leucemia de células T do adulto (ATLL) é um tipo raro de linfoma causado pelo vírus T-linfotrópico humano tipo I (HTLV-1). O quadro clínico inclui lesões de pele, adenomegalias, mielopatia/paraparesia espástica tropical, uveíte, doença oftalmológica, leucocitose com linfocitose e linfócitos atípicos. O objetivo deste estudo foi relatar o caso de uma paciente com ATLL, agricultora, com leucocitose, linfocitose, eritema ocular bilateral, linfadenopatia cervical, sem visceromegalias abdominais e com marcadores positivos para linfócitos T (CD45, CD2, CD3, CD5, CD4 e CD25). Embora a ATLL seja uma doença rara, a demora no seu diagnóstico pode levar a sérias complicações e ocasionar a morte do paciente.

Estudo da influência dos alelos do HLA classe I e II e do polimorfismo dos genes de citocinas na infecção pelo HTLV-1 / Study of the influence of hla class i and ii alleles and the polymorphism of cytokines genes in htlv-1 infection

O vírus linfotrópico para células T humanas (HTLV-1) é o principal agente causador da Paraparesia Espástica Tropical / Mielopatia associada ao HTLV-1 (PET/MAH) e da Leucemia da célula T do Adulto (LTA). [...]Fatores da interação HTLV-1/ hospedeiro estão envolvidos no risco de desenvolver doença. A lesão neurológica na PET/MAH parece ser consequência de uma reação inflamatória, desencadeada pelo reconhecimento de células infectadas por linfócitos T citotóxicos, com consequente liberação de citocinas e lesão medular. OBJETIVO: Identificar marcadores genéticos, que possam ajudar no prognóstico e tratamento dos pacientes portadores do HTLV-1. MÉTODOS: Nas amostras de 117 portadores do HTLV-1 assintomáticos e 171 pacientes com acometimento neurológico em acompanhamento na cidade do Rio de Janeiro, foram realizadas as tipificações dos genes do HLA Classe I e II, dos polimorfismos dos genes das citocinas -308TNF-α,-174IL-6, +874IFN-γ, códon 10 e 25TGF-β1 e -1082 - 819-592IL-10, e a quantificação da carga proviral. Os dados foram organizados em um banco de dados no programa SPSS. As frequências alélicas e genotípicas foram obtidas por contagem direta. O equilíbrio de Hardy-Weinberg foi avaliado para os polimorfismos das citocinas no sitio http://bioinfo.iconcologia.net/ubbweb/SNPStats_web, em relação ao HLA foram utilizadas as ferramentas disponíveis no sítio “Los Alamos HIV database tools”. As comparações entre os grupos foram realizadas através de tabelas de contingência 2x2 (quiquadrado, exato de Fisher e odds ratios), valores de p≤0,05 foram considerados significantes...

The human T cell lymphotropic vírus (HTLV-1) is the main causingagent of Tropical Spastic Paraparesis/HTLV-1 Associated Myelopathy (HAM/TSP) aswell as of Adult T Cell Leukemia (ATL). [...] Factorsrelated to the HTLV-1/host interaction may be involved in the risk of developing thediseases. The neurological lesion in HAM/TSP may be the consequence of aninflammatory reaction, triggered by the recognition of infected cells by cytotoxic Tlymphocytes, followed by the release of cytokines and central nervous system lesion.OBJECTIVE: This work aims to identify genetic markers, which may help in theprognosis and treatment of HTLV-1 patients. Methods: The polymorphism of the HLAClass I and II genes, as well as the TNF-α, IL6, IFN-γ, TGF-β and IL-10 cytokinegenes, and the proviral load were analysed in 117 asymptomatic HTLV-1 carriersand 171 HTLV-1 symptomatic carriers from Rio de Janeiro city. Data were organizedinto a database using SPSS. The Hardy-Weinberg equilibrium was evaluated forcytokine polimorphisms using the site http://bioinfo.iconcologia.net/ubbweb/SNPStats_web. The tools available in the site “Los Alamos HIV database tools” were used toanalyze the HLA polimorphisms. Comparisons between groups were made using 2x2contingency tables (Fisher Exact test/ χ2 and odds ratios), p values p≤0,05 wereconsidered significant...

Silencing HIF-1α reduces the adhesion and secretion functions of acute leukemia hBMSCs

Hypoxia inducible factor-1α (HIF-1α) is an important transcription factor, which plays a critical role in the formation of solid tumor and its microenviroment. The objective of the present study was to evaluate the expression and function of HIF-1α in human leukemia bone marrow stromal cells (BMSCs) and to identify the downstream targets of HIF-1α. HIF-1α expression was detected at both the RNA and protein levels using real-time PCR and immunohistochemistry, respectively. Vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α) were detected in stromal cells by enzyme-linked immunosorbent assay. HIF-1α was blocked by constructing the lentiviral RNAi vector system and infecting the BMSCs. The Jurkat cell/BMSC co-cultured system was constructed by putting the two cells into the same suitable cultured media and conditions. Cell adhesion and secretion functions of stromal cells were evaluated after transfection with the lentiviral RNAi vector of HIF-1α. Increased HIF-1α mRNA and protein was detected in the nucleus of the acute myeloblastic and acute lymphoblastic leukemia compared with normal BMSCs. The lentiviral RANi vector for HIF-1α was successfully constructed and was applied to block the expression of HIF-1α. When HIF-1α of BMSCs was blocked, the expression of VEGF and SDF-1 secreted by stromal cells were decreased. When HIF-1α was blocked, the co-cultured Jurkat cell’s adhesion and migration functions were also decreased. Taken together, these results suggest that HIF-1α acts as an important transcription factor and can significantly affect the secretion and adhesion functions of leukemia BMSCs.

Isolated relapse in the oral cavity of a child with t-lineage acute lymphoblastic leukemia

Despite high cure rates, approximately 20% of patients with acute lymphoblastic leukemia (ALL) have disease relapse. Isolated recurrence in oral cavity is extremely unusual. The aim of this paper is to report a case of an isolated relapse occurred in a child with T-lineage ALL. Clinical picture included swelling and pain in the right upper gingiva of the oral cavity, with no other clinical or hematological alterations. Diagnosis was confirmed by biopsy and immunohistochemical staining. Bone marrow aspiration was normal. Five months later leukemic infiltration of the bone marrow was detected and systemic chemotherapy was reintroduced. This case report highlights the relevance of dental care during and after chemotherapy, not only to treat lesions in the oral cavity resulting from the disease itself or from treatment side effects, but also to detect unusual sites of ALL relapse.

Apesar dos altos índices de cura, cerca de 20% dos pacientes com leucemia linfóide aguda (LLA) apresentam recidiva da doença. Recidiva isolada na cavidade oral é extremamente incomum. O objetivo deste trabalho é relatar um caso de recidiva isolada em criança com LLA de linhagem T. A apresentação clínica foi quadro de edema e dor na cavidade oral, na região superior da gengiva à direita, sem outras alterações clínicas ou hematológicas. O diagnóstico foi confirmado por meio de biópsia e imuno-histoquímica. O mielograma era normal. Cinco meses após a manifestação inicial na cavidade oral, foi detectada infiltração leucêmica na medula óssea. O tratamento com quimioterapia sistêmica foi reintroduzido. Este relato de caso ressalta a importância do acompanhamento clínico e odontológico durante e após o tratamento quimioterápico, não somente com o objetivo de tratar as alterações na cavidade oral decorrentes da própria doença ou dos efeitos adversos do tratamento, mas para que sejam detectadas apresentações incomuns de recidiva na LLA.

Estudo de alterações genéticas associadas à leucemia/linfoma de células T do adulto no Estado da Bahia / Study of genetic alterations associated with leukemia / lymphoma, adult T-cell in the State of Bahia

A leucemia/linfoma de células T do adulto (ATL) é uma severa doença linfoproliferativa de células T CD4+ associada ao HTLV-1. Por apresentar diferentes manifestações clínicas, essa neoplasia pode ser classificada em cinco formas: aguda, crônica, smoldering, linfomatosa e tumoral primária de pele. Embora alguns trabalhos venham estudando o processo oncogênico mediado pelo HTLV-1, diversos fatores responsáveis pelo desenvolvimento da ATL ainda permanecem desconhecidos. Este estudo teve como objetivo a investigação de alterações genéticas em células ATL (mutações pontuais em genes supressores de tumor e alterações microssatélites) e sua associação com a evolução clínica da doença e sobrevida dos pacientes. A presença de mutações pontuais nos supressores de tumor TP53, p15INK4B e p16INK4A foram avaliadas em 31 pacientes com diferentes formas da ATL (16 agudos, dez crônicos e cinco smoldering) por análise de seqüenciamento de DNA. Cinco pacientes (16%) apresentaram mutações pontuais no gene TP53, sendo que quatro dentre os mesmos foram classificados com a forma aguda. A presença de mutações nos genes avaliados foi associada com pior prognóstico em pacientes com a forma aguda. Em um dos pacientes incluídos neste trabalho (forma aguda) foi verificada a presença de alteração no éxon 2 do gene p16INK4A. Mutações pontuais não foram detectadas no gene p15INK4B em nenhum dos pacientes incluídos. Os marcadores D10S190, D10S191, D11S1391 e D18S21 foram utilizados para a análise de alterações microssatélites por metodologia semi-automatizada. Dentre os 25 pacientes ATL avaliados (seis agudos, oito crônicos, dez smoldering e um linfomatoso), sete apresentaram alterações microssatélites. Três desses pacientes apresentaram instabilidade (MSI), três pacientes apresentaram perda de heterozigosidade (LOH) e em um paciente foi verificado ambas as alterações. Na Bahia, mutações pontuais em TP53 foram detectadas principalmente na forma aguda da ATL e parece estar associada com pior prognóstico. Além disso, de acordo com nossos conhecimentos, este é o primeiro estudo a descrever tanto MSI com LOH em pacientes portando formas crônica e smoldering da ATL.

Leucemia linfoma de células T del adulto y linfoma cutáneo asociados al HTLV-1 / Adult T-cell leukemia/lymphoma and cutaneous lymphoma associated to HTLV-1

El virus linfotrópico humano tipo 1 (HTLV-1) se adquiere a través de la lactancia prolongada, contacto sexual e infusión sanguínea, entre el 1-4% de los infectados desarrollan Linfoma Leucemia de Células T del Adulto (LLCTA) con un periodo de latencia entre 30 y 50 años, siendo incurable y mortal a corto plazo, las causas de muerte más frecuentes son infecciones, el linfoma cutáneo de células T es otra manifestación del virus, indicando diseminación. Se presenta el caso de un hombre de 51 años, con hiporexia, odinofagia, lesiones ulceradas necróticas en manos, tórax y cabeza, micosis oral, ingresa por hematemesis, hematoquecia y astenia, presenta, anemia, alteraciones nutricionales y neurológicas. El estudio hematológico diagnosticó LLCTA y la biopsia linfoma cutáneo de células T. El paciente tendría un pronóstico desfavorable.

The human virus T-lymphtrophic (HTLV-1) is acquired through prolonged breastfeeding, sexual contact and blood infusion. Between 1% to 4% of those infected, develop Adult T-cell leukemia/lymphoma (ATL) during the latency period between 30 to 50 years, it is still incurable and most of the cases end with fatal dead in the short term, the most frequent causes of death are infections. The cutaneous T-cell lymphoma is another manifestation of the virus, indicating spread. 51 year old male, with hyporexia, odynophagia, necrotic ulcerated lesions on the hands, chest and head, presents oral fungal, enters with hematemesys, hematoquesia and asthenia, anemia, nutritional and neurological disorders. Hematological tests cutaneous T -cell lymphoma cutaneous, respectively. The patient would have an unfavorable prognosis.

The clinical and laboratory features of 9 cases with gammadeltaT cell lymphoma or leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the clinical and laboratory features of 9 cases of gammadeltaT cell lymphoma or leukemia.</p><p><b>METHODS</b>From 2007 to 2011, 9 patients with gammadeltaT-cell lymphoma/leukemia were diagnosed in our hospital. The immunophenotype of the abnormal cells were detected by flow cytometry, clonal gene rearrangement of IgH, TCRgamma, TCRdelta by PCR, chromosome karyotype analysis by G banding, acute leukemia gene and the DNA of type 1 - 8 human herpes virus by multiple nested PCR, The gammadeltaT cells were determined by T cell with TCR gammadelta chain, the malignant gammadelta T cells by the abnormal expression of T cell antigens and the precursor malignant gammadelta T cells by the expression of CD34, TDT, CD99, CD1 a or acute leukemia genes.</p><p><b>RESULTS</b>In the 9 patients with gammadeltaT cell lymphoma leukemia, significant malignant gammadeltaT cells infiltration of bone marrow were found in 8 with blast morphology. 5 were diagnosed as T-ALL/LBL (gammadeltaT type) and 4 HSgammadelta TCL. The clonal gene rearrangement of TCRgamma and/or TCRB were detected in 6/6 patients. Patients either did not achieve complete remission(CR) after induction therapy or relapsed quickly after CR. Only 4/5 patients remained continuous CR(CCR) at 2, 2, 3,12 months respectively, after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the fifth T-ALL (gammadeltaT) relapsed 1 month after allo-HSCT.</p><p><b>CONCLUSIONS</b>The incidence of gammadelta T cell lymphoma or leukemia may be higher than reported, part of them were T-ALL/LBL with poor prognoses. FCM and clonal gene rearrangement of TCRgamma and/or TCRdelta are helpful to diagnosis. Allo-HSCT may be the only curative approach.</p>

Leucemia de células T do adulto / Adult T-cell leukemia

A leucemia de células T no adulto (ATL) é causada pelo vírus linfotrópico de células T (HTLV-1). Contudo, apenas 2 por cento-5 por cento dos indivíduos infectados desenvolvem a ATL e somente 40-60 anos após a infecção. Um fator de risco para adquirir a doença é a via da transmissão do vírus pela amamentação e durante o parto, sugerindo que a criança já é portadora do vírus. Desde a descoberta do vírus, em 1980, vários artigos científicos foram publicados descrevendo as manifestações clínicas, biologia do vírus e alterações intracelulares induzidas pelo vírus. Esta revisão visa explorar alguns aspectos da relação entre HTLV-1 e a leucemia de células T do Adulto.

The human T-lymphotropic virus (HTLV-1) is known to be the etiologic agent of adult T-cell leukemia (ATL). Only 2-5 percent of infected individuals develop ATL and even then only 40-60 years after infection. One risk factor to develop ATL is the transmission of the virus by breastfeeding and during delivery, suggesting that infants of infected mothers are already carriers of the virus. Since the discovery of the virus in 1980 many scientific papers have been published describing the clinical manifestations, biology of the virus and the intracellular alterations induced by the virus. This review aims to explore some aspects of the relationship between HTLV-1 and ATL.

Mesenchymal stem cells do not suppress lymphoblastic leukemic cell line proliferation

Several studies have demonstrated the immunosuppresive effects of mesenchymal stem cells [MSCs] in allogeneic or mitogenic interactions. Cell-cell contact inhibition and secretion of suppressive soluble factors have been suggested in this regard. To investigate if adipose derived MSCs could inhibit Jurkat lymphoblastic leukemia T cell proliferation during coculture. Adherent cells with the ability of cellular growth were isolated from normal adipose tissues. Initial characterization of growing cells by flow cytometry suggested their mesenchymal stem cell characteristics. Cells were maintained in culture and used during third to fifth culture passages. Jurkat or allogeneic peripheral blood mononuclear cells [PBMCs] were labeled with carboxy fluorescein diacetate succinimidyl ester and cocultured with increasing doses of MSCs or MSC culture supernatant. Proliferation of PBMCs or Jurkat cells under these conditions was assessed by flow cytometry after 2 and 3 days of coculture, respectively. Results showed the expression of CD105, CD166 and CD44, and the absence of CD45, CD34 and CD14 on the surface of MSC like cells. Moreover, initial differentiation studies showed the potential of cell differentiation into hepatocytes. Comparison of Jurkat cell proliferation in the presence and absence of MSCs showed no significant difference, with 70% of cells displaying signs of at least one cell division. Similarly, the highest concentration of MSC culture supernatant [50% vol/vol] had no significant effect on Jurkat cell proliferation [p>0.6]. The same MSC lots significantly suppressed the allogeneic PHA activated PBMCs under similar culture conditions. Using Jurkat cells as a model of leukemia T cells, our results indicated an uncertainty about the suppressive effect of MSCs and their inhibitory metabolites on tumor or leukemia cell proliferation. Additional systematic studies with MSCs of different sources are needed to fully characterize the immunological properties of MSCs be-fore planning clinical applications

El virus linfotropico HTLV-1: un problema emergente en Bolivia / The lymphotropic HTLV-1 virus: an emergent problem in Bolivia

En los últimos años nos hemos venido preguntando, ¿ existen nuevas enfermedades o simplemente estamos redescubriendo algunas? Esto lleva a la necesidadde generar el término de Enfermedades Emergentes, refiriéndonos a aquellas enfermedades nuevas opreviamente descritas que se hacen importantes porsu incidencia creciente.1Tajima y Sonoda, han planteado un nuevo enfoque en el conocimiento de ciertas enfermedades que hanafectado al ser humano desde épocas antiguas, denominando a esta disciplina etnoepidemiología. 2,3Una entidad digna de estos estudios es el Virus Linfotrófico Humano Tipo 1 (HTLV-1), ya que su descubrimiento en varias partes del mundo, apoya la hipótesis de la migración de los pueblos, portadores de este virus, a través del Estrecho de Bering, llegando hasta las más remotas regiones del sur del continente americano, sin descartar la posibilidad de otras migraciones posteriores por vía marítima

Modulation of Apoptosis and Cell Cycle by Synthetic Bile Acid Derivatives / 대한해부학회지

This paper outlines the current understanding of cell cycle modulation and induction of apoptosis in cancer cells by natural and synthetic bile acid. Bile acid homeostasis is tightly regulated in health, and the cellular and tissue concentrations of bile are restricted. However, when pathophysiological processes impair biliary secretion, hepatocytes are exposed to an elevated concentration of bile acids, which triggers cell death. In this context, we have synthesized several new bile acid derivatives. These synthetic bile acids modulate the cell cycle and induce apoptosis in several human cancer cells similar to the effects of natural bile acids. In human breast and prostate cancer cells with different tumor suppressor p53 status, synthetic bile acid induced growth inhibition and apoptosis, and these changes were associated with upregulation of Bax and p21WAF1/CIP1 through a p53-independent pathway. In Jurkat human T cell leukemia cells, the synthetic bile acids induced apoptosis through caspase activation. The synthetic bile acids induced apoptosis in a JNK-dependent manner in SiHa human cervical cancer cells through the induction of Bax and activation of caspases in PC3 prostate cancer cells and induction of G1 phase arrest of the cell cycle in HT29 colon cancer cells. The synthetic bile acids also induced apoptosis in four human glioblastoma multiform cell lines (e.g., U-118MG, U-87MG, T98G, and U-373MG) and one human TE671 medulloblastoma cell line. A chenodeoxycholic acid derivative, called HS-1200, significantly decreased the growth of TE671 medulloblastoma tumor size and increased lifespan in nonobese diabetic and severe combined immunodeficient (NOD/SCID) mice. These findings suggest that these new synthetic bile acids, which are novel apoptosis mediators, might be applicable to the treatment of various human cancer cells.