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Detección de anticuerpos contra la proteína de fusión PML/RARa en la leucemia promielocítica: /RARa fusion protein in promyelocytic leukemia Detection of antibodies to PM:  [cached]
Rinaldo Villaescusa Blanco,Ada A Arce Hernández,Julio C Merlín Linares,Ana M Guerreiro Hernández
Revista Cubana de Hematolog?-a, Inmunolog?-a y Hemoterapia , 2010,
Abstract: La leucemia promielocítica (LPM) está asociada con características genéticas únicas que incluyen la translocación recíproca t(15;17)(q22;q12) con la formación del complejo PML-RARa, el cual representa más del 95 % de las proteínas de fusión en la LPM y resulta una diana potencial de la respuesta inmune. Los tratamientos actuales conocidos por terapias de diferenciación combinan el ácido trans retinoico (ATRA) y las antraciclinas, así como el trióxido de arsénico; resultan en una sobrevida a largo plazo y la cura potencial aproximadamente entre el 70 y 80 % de los pacientes. En estudios realizados en ratones con LPM inmunizados con una vacuna de ADN elaborada mediante la fusión del oncogen PML-RARa al fragmento C de la toxina tetánica como adyuvante, conjuntamente con ATRA, se produjeron títulos elevados de anticuerpos. Se logró una sobrevida significativa, entre 120-300 días, comparada con la de ratones a los que se administró placebo. En nuestro trabajo se detectó la presencia de anticuerpos contra la proteína de fusión PML-RARa en diferentes fases del tratamiento, lo que indica la capacidad de respuesta de estos pacientes frente al antígeno tumoral. Los anticuerpos anti PML-RARa se detectaron en aquellos pacientes sin tratar y en fase de inducción, no así en la consolidación y mantenimiento, de ahí su posible utilidad como marcador de diferenciación celular a partir de la presencia o ausencia de la proteína de fusión en la célula leucémica. Promyelocytic leukemia (PML) is associated with unique genetic features including the t reciprocal translocation (15; 17) (q22; q22) with PML-RARa, which accounted for more than 95 % of fusion protein in PML and is a potential target of immune response. The current treatments known as differentiation therapies combine the trans-retinoic acid (TRA) and the anthracyclines, as well as the trioxide arsenic (As(2)0(3)); become in a long-term survival and the potential cure in about the 70 to 80 % of patients. In studies conducted in LPM-mice immunized with a DNA vaccine made the PML-RARa oncogene fusion to C fragment of tetanus toxin as coadjuvant together with TRA were antibodies high titers. It was possible to achieve a significant survival among 120-130 days compared with that of placebo-mice. In our paper it was detected the presence of antibodies to PML-RARa fusion protein in different phases of treatment indicating the response to these patients to tumor antibody. The anti-PML-RARa were detected in those non-treated patients and in induction fusion, but not in consolidation and maintenance, thus its potential usef
Detección de anticuerpos contra la proteína de fusión PML/RARa en la leucemia promielocítica: /RARa fusion protein in promyelocytic leukemia
Villaescusa Blanco,Rinaldo; Arce Hernández,Ada A; Merlín Linares,Julio C; Guerreiro Hernández,Ana M; Socarrás Ferrer,Beatriz; del Valle Pérez,Lázaro O; Macías Abraham,Consuelo; Lam Díaz,Rosa M; Hernández Ramírez,Porfirio;
Revista Cubana de Hematolog?-a, Inmunolog?-a y Hemoterapia , 2010,
Abstract: promyelocytic leukemia (pml) is associated with unique genetic features including the t reciprocal translocation (15; 17) (q22; q22) with pml-rara, which accounted for more than 95 % of fusion protein in pml and is a potential target of immune response. the current treatments known as differentiation therapies combine the trans-retinoic acid (tra) and the anthracyclines, as well as the trioxide arsenic (as203); become in a long-term survival and the potential cure in about the 70 to 80 % of patients. in studies conducted in lpm-mice immunized with a dna vaccine made the pml-rara oncogene fusion to c fragment of tetanus toxin as coadjuvant together with tra were antibodies high titers. it was possible to achieve a significant survival among 120-130 days compared with that of placebo-mice. in our paper it was detected the presence of antibodies to pml-rara fusion protein in different phases of treatment indicating the response to these patients to tumor antibody. the anti-pml-rara were detected in those non-treated patients and in induction fusion, but not in consolidation and maintenance, thus its potential usefulness as cellular differentiation marker from presence or absence of fusion protein un leukemic cell.
Estudio piloto de la fusión PML/RARalfa por el método de hibridación in situ con fluorescencia (FISH) en leucemia aguda promielocítica Pilot study of PML/RARalpha fusion by fluorescence in situ hybridization (FISH) method in acute promyelocytic leukemia  [cached]
María Eugenia Legües S,Giannina Franco C,Pablo Bertin C
Revista médica de Chile , 2002,
Abstract: Background: Acute promyelocytic leukemia (APL) is characterized cytogenetically by t(15;17) (q22;q21) and its molecular consequence, fusion of PML and RARalpha genes. The detection of this genetic marker confirms the diagnosis and allows monitoring of the leukemic clone during treatment, which has prognostic value. Cytogenetics fails in some cases due to the absence of metaphases in cultures or their bad morphology. Southern blot and PCR methods require trained personnel and adequate equipment. FISH method allows the identification of chromosomic rearrangements in 24 to 48 h and is simple to set up in a cytogenetics laboratory. Aim: To evaluate the FISH method to detect PML/RARalpha fusion, compared to cytogenetic analysis. Patients and methods: Fifteen bone marrow specimens from APL patients with previous cytogenetic analysis were studied, using a commercial probe to detect PML/RARalpha fusion. Results: We obtained a normal cut-off value of 9.1%. Specificity and sensibility were 100%. Six positive cytogenetic cases at diagnosis were FISH positive. Six negative cytogenetic cases, one APL at diagnosis and five normal controls were FISH negative. One case in remission, that was negative by cytogenetics, was positive near the cut-off value by FISH. Two other cases in remission, not conclusive by cytogenetics, were negative by FISH. Conclusions: FISH is a reliable, rapid and relatively low cost method that can be used as an adjunct to conventional cytogenetics (Rev Méd Chile 2002; 130: 737-44)
Diagnóstico molecular de la leucemia aguda promielocítica: Resultados preliminares Molecular diagnosis of acute promyelocytic leukemia: preliminary results
Gisela Martínez Antu?a,Niubys Cayado Gutiérrez,Adriana Mu?iz Fernández,Edgardo Espinosa Martínez
Revista Cubana de Hematolog?-a, Inmunolog?-a y Hemoterapia , 2000,
Abstract: La leucemia aguda promielocítica (LAP) se caracteriza por la presencia de la translocación recíproca t (15;17) que tiene como resultado la formación del gen híbrido PML-RARa . Como la LAP se considera una emergencia hematológica y además tiene hoy en día un tratamiento muy específico con ácido retinoico (ATRA), es muy importante hacer un diagnóstico rápido y preciso, que en muchos casos permite incluso salvar la vida del paciente. En la actualidad se han desarrollado métodos de RT-PCR para detectar el gen híbrido PML-RARa . Estas técnicas moleculares han sido extremadamente útiles en el diagnóstico de esta entidad. En este trabajo presentamos los resultados preliminares del diagnóstico molecular en 38 pacientes con LAP. En 36 pacientes se demostró la presencia del gen híbrido y 2 fueron negativos. Del total de enfermos con resultados positivos, 19 (55 %) fueron bcr 1, 2 (5 %) fueron bcr 2 y 14 (40 %) fueron bcr 3. Todos los pacientes con resultados positivos respondieron al tratamiento con ATRA. En 1 de los 2 pacientes con resultados negativos se demostró la presencia de la t(11;17). Ninguno de estos 2 enfermos respondió al tratamiento con ATRA Acute promyelocytic leukemia (APL) is characterized by the reciprocal translocation t(15; 17) that results in fusion gene PML-RARa formation. As APL is considered to be an hematological emergency and also is given a very specific treatment with retinoic acid (ATRA), then it is very important to diagnose quickly and accurately which makes it possible in many cases to save the patient's life. At present RT- PCR methods have been developed to detect PML-RARa gen. These molecular techniques have been extremely useful in diagnosing this entity. This paper sets forth the preliminary results of molecular diagnoses of APL in 38 patients. 36 cases presented the fusion gene and 2 did not. Of the total number of positive patients, 19(55%) were bcr 1, 2 (5%) were bcr 2 and 14(40%) bcr 3. All the patients with positive results were responsive to treatment with ATRA. One of the two patients with negative results showed the existence of t (11; 17). These two patients did not respond to treatment with ATRA
Trióxido de arsénico: una nueva luz en el tratamiento de la leucemia promielocítica Arsenic trioxide: a new light in the treatment of promyelocytic leukemia  [cached]
Carlos Hernández Padrón,Edgardo Espinosa Martínez,Rafael Losada Buchillón,Onel ávila Cabrera
Revista Cubana de Hematolog?-a, Inmunolog?-a y Hemoterapia , 2008,
Abstract: En los últimos 20 a os, y gracias a la efectividad del ácido retinoico todo en trans (ATRA), medicamento introducido por investigadores chinos en el tratamiento de la leucemia promielocítica, esta variedad de leucemia pasó de ser la más agresiva y de peor pronóstico por su alta mortalidad, a ser en la que se logra una mayor sobrevida y posibilidad de curación; pero a pesar de las bondades de este medicamento, aproximadamente el 20 % de los pacientes pueden tener una recaída tanto hematológica como molecular en algún momento de la evolución de la enfermedad. Nuevamente investigadores chinos demostraron los beneficios del trióxido de arsénico (TOA), medicamento que por diferentes vías logra la maduración y diferenciación del promielocito leucémico y finalmente la desaparición del gen anormal PML/RARá y de su proteína híbrida. En los primeros trabajos realizados, el trióxido de arsénico se utilizó en los pacientes que tenían algún tipo de recaída o en aquellos que no respondían al ATRA y se logró alrededor del 80 % de remisiones hematológicas y moleculares en estos enfermos; posteriormente varios grupos de trabajo han reportado resultados similares. Ante estos resultados, el TOA se comenzó a utilizar como droga de primera línea con excelentes resultados. In the last 20 years and thanks to the effectivity of all-trans retinoic acid (ATRA), a drug introduced by Chinese researchers in the treatment of promyelocytic leukemia, this variety of leukemia that was the most aggressive and had the poorest prognosis due to its high mortality, has showed the highest survival and possibility of cure. In spite of its benefits, at about 20 % of the patients may have a relapse both hematological and molecular some time during the evolution of the disease. Once again, the Chinese researchers showed the benefits or arsenic trioxide, a drug that allows by different routes the maturation and differentiation of leukemic promyelocite and, finally, the disappearance of the abnormal PML/RAR? gene and of its hybrid protein. In the first trials, arsenic trioxide was used in patients with some type of relapse or in those who did not respond to ATRA. 80 % of hematological and molecular remissions were observed in these patients. Similar outcomes have been reported by various groups. According to its effects, it is being used as a first-line drug with excellent results.
Targeting Promyelocytic Leukemia Protein: A Means to Regulating PML Nuclear Bodies
Erin L. Reineke, Hung-Ying Kao
International Journal of Biological Sciences , 2009,
Abstract: The promyelocytic leukemia protein (PML) is involved in many cellular processes including cell cycle progression, DNA damage response, transcriptional regulation, viral infection, and apoptosis. These cellular activities often rely on the localization of PML to unique subnuclear structures known as PML nuclear bodies (NBs). More than 50 cellular proteins are known to traffic in and out of PML NBs, either transiently or constitutively. In order to understand the dynamics of these NBs, it is important to delineate the regulation of PML itself. PML is subject to extensive regulation at transcriptional, post-transcriptional, and post-translational levels. Many of these modes of regulation depend on the cellular context and the presence of extracellular signals. This review focuses on the current knowledge of regulation of PML under normal cellular conditions as well as the role for regulation of PML in viral infection and cancer.
Detection of Promyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARα) Fusion Gene with Functionalized Graphene Oxide  [PDF]
Ran Li,Yanhong Tan,Xiuhua Chen,Fanggang Ren,Yaofang Zhang,Zhifang Xu,Hongwei Wang
International Journal of Molecular Sciences , 2013, DOI: 10.3390/ijms140612863
Abstract: An attempt was made to use functionalized graphene oxide (GO) to detect the Promyelocytic leukemia/Retinoic acid receptor α fusion gene ( PML/RAR α fusion gene), a marker gene of acute promyelocytic leukemia. The functionalized GO was prepared by chemical exfoliation method, followed by a polyethylene glycol grafting. It is found that the functionalized GO can selectively adsorb the fluorescein isothiocyanate (FITC)-labeled single-stranded DNA probe and quench its fluorescence. The probe can be displaced by the PML/RARα fusion gene to restore the fluorescence, which can be detected by laser confocal microscopy and flow cytometry. These can be used to detect the presence of the PML/RAR α fusion gene. This detection method is verified to be fast, simple and reliable.
Targeting the Acute Promyelocytic Leukemia-Associated Fusion Proteins PML/RARα and PLZF/RARα with Interfering Peptides  [PDF]
Sabine Beez, Philipp Demmer, Elena Puccetti
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048636
Abstract: In acute promyelocytic leukemia (APL), hematopoietic differentiation is blocked and immature blasts accumulate in the bone marrow and blood. APL is associated with chromosomal aberrations, including t(15;17) and t(11;17). For these two translocations, the retinoic acid receptor alpha (RARα) is fused to the promyelocytic leukemia (PML) gene or the promyelocytic zinc finger (PLZF) gene, respectively. Both fusion proteins lead to the formation of a high-molecular-weight complex. High-molecular-weight complexes are caused by the “coiled-coil” domain of PML or the BTB/POZ domain of PLZF. PML/RARα without the “coiled-coil” fails to block differentiation and mediates an all-trans retinoic acid-response. Similarly, mutations in the BTB/POZ domain disrupt the high-molecular-weight complex, abolishing the leukemic potential of PLZF/RARα. Specific interfering polypeptides were used to target the oligomerization domain of PML/RARα or PLZF/RARα. PML/RARα and PLZF/RARα were analyzed for the ability to form high-molecular-weight complexes, the protein stability and the potential to induce a leukemic phenotype in the presence of the interfering peptides. Expression of these interfering peptides resulted in a reduced replating efficiency and overcame the differentiation block induced by PML/RARα and PLZF/RARα in murine hematopoietic stem cells. This expression also destabilized the PLZF/RARα-induced high-molecular-weight complex formation and caused the degradation of the fusion protein. Targeting fusion proteins through interfering peptides is a promising approach to further elucidate the biology of leukemia.
Posible quimera M3: M5 en un paciente con leucemia aguda promielocítica; diferente respuesta clonal al tratamiento con ANTRA y quimioterapia Probable chimera M3: M5 in an acute promyelocytic leukemia patient; different clonal response to treatment with transretinoic acid and chemotherapy
Niubys Cayado Gutiérrez,Carlos Hernández Padrón,Luis Gabriel Ramón Rodríguez,Porfirio Hernández Ramírez
Revista Cubana de Hematolog?-a, Inmunolog?-a y Hemoterapia , 2004,
Abstract: Se presenta un caso con leucemia aguda promielocítica (LAP) en el que se demostró la presencia del gen híbrido PML/RARa y la duplicación interna en tandem del gen FLT3 (DIT/FLT3) al momento del diagnóstico. Después de recibir tratamiento de inducción con ácido transretinoico (ATRA) y quimioterapia, el estudio citomorfológico de la médula ósea mostró una transformación a leucemia monocítica aguda (LMA-M5). En el estudio molecular desapareció el transcripto PML/RARa, pero se mantuvo la DIT/FLT3. Estos resultados sugieren la coexistencia de 2 clones leucémicos independientes, un clon promielocítico (M3) con el gen quimérico PML/RARa y otro monocítico (M5) con DIT/FLT3. Aunque la evolución hematológica y molecular apoya esta sugerencia, no se puede excluir la presencia de la DIT/FLT3 en el clon M3, pues no es un marcador específico de la LMA-M5 A case of acute promyelocytic leukemia in which the presence of hybrid PML/RAR a gene and the internal tandem duplication of FLT3 (DIT/FLT3)were demonstrated at the time of diagnosis was reported in this paper. After the induction treatment with transretinoic acid and chemotherapy, the cytomorphological study of the bone marrow revealed some change into acute monocytic leukemia (AML-M5). The molecular study revealed that PML/RARa had disappeared but ITD/FLT3 remained. These results suggest that two independent leukemia clones co-exist, that is, one promyeolytic (M3) with chimeric gene PML/RARa and the other monocytic (M5) with ITD/FLT3). Although the hematological and molecular evolution supports such a suggestion, the presence of ITD/FLT3 in clone M3 can not be ignored because it is not a specific marker for AML-M5
Microarray analysis revealing common and distinct functions of promyelocytic leukemia protein (PML) and tumor necrosis factor alpha (TNFα) signaling in endothelial cells  [cached]
Cheng Xiwen,Kao Hung-Ying
BMC Genomics , 2012, DOI: 10.1186/1471-2164-13-453
Abstract: Background Promyelocytic leukemia protein (PML) is a tumor suppressor that is highly expressed in endothelial cells nonetheless its role in endothelial cell biology remains elusive. Tumor necrosis factor alpha (TNFα) is an important cytokine associated with many inflammation-related diseases. We have previously demonstrated that TNFα induces PML protein accumulation. We hypothesized that PML may play a role in TNFα signaling pathway. To identify potential PML target genes and investigate the putative crosstalk between PML’s function and TNFα signaling in endothelial cells, we carried out a microarray analysis in human primary umbilical endothelial cells (HUVECs). Results We found that PML and TNFα regulate common and distinct genes involved in a similar spectrum of biological processes, pathways and human diseases. More importantly, we found that PML is required for fine-tuning of TNFα-mediated immune and inflammatory responses. Furthermore, our data suggest that PML and TNFα synergistically regulate cell adhesion by engaging multiple molecular mechanisms. Our biological functional assays exemplified that adhesion of U937 human leukocytes to HUVECs is co-regulated by PML and TNFα signaling. Conclusions Together, our study identified PML as an essential regulator of TNFα signaling by revealing the crosstalk between PML knockdown-mediated effects and TNFα-elicited signaling, thereby providing novel insights into TNFα signaling in endothelial cells.
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