Epigenetics in acute promyelocytic leukaemia pathogenesis and treatment response: a TRAnsition to targeted therapies.

Transcriptional deregulation plays a key role in a large array of cancers, and successful targeting of oncogenic transcription factors that sustain diseases has been a holy grail in the field. Acute promyelocytic leukaemia (APL) driven by chimeric transcription factors encoding retinoic acid receptor alpha fusions is the paradigm of targeted cancer therapy, in which the application of all-trans retinoic acid (ATRA) treatments have markedly transformed this highly fatal cancer to a highly manageable disease. The extremely high complete remission rate resulted from targeted therapies using ATRA in combination with arsenic trioxide will likely be able to minimise or even totally eliminate the use of highly toxic chemotherapeutic agents in APL. In this article, we will review the molecular basis and the upcoming challenges of these targeted therapies in APL, and discuss the recent advance in our understanding of epigenetics underlying ATRA response and their potential use to further improve treatment response and overcome resistance.

MN1-Fli1 oncofusion transforms murine hematopoietic progenitor cells into acute megakaryoblastic leukemia cells.

Long-term outcome of acute megakaryoblastic leukemia (AMKL) patients without Down's syndrome remains poor. Founding mutations and chimeric oncogenes characterize various AMKL subtypes. However, for around one third of all cases the underlying mechanisms of AMKL leukemogenesis are still largely unknown. Recently, an in-frame fusion of meningeoma 1-friend leukemia virus integration 1 (MN1-Fli1) gene was detected in a child with AMKL. We intended to investigate the potential role of this oncofusion in leukemogenesis of acute myeloid leukemia. Strikingly, expression of MN1-Fli1 in murine hematopoietic progenitor cells was sufficient to induce leukemic transformation generating immature myeloid cells with cytomorphology and expression of surface markers typical for AMKL. Systematic structure function analyses revealed FLS and 3'ETS domains of Fli1 as decisive domains for the AMKL phenotype. Our data highlight an important role of MN1-Fli1 in AMKL leukemogenesis and provide a basis for research assessing the value of this oncofusion as a future diagnostic marker and/or therapeutic target in AMKL patients.

Regeneration influences expression of the Na+, K+-atpase subunit isoforms in the rat peripheral nervous system.

Neural injury triggers changes in the expression of a large number of gene families. Particularly interesting are those encoding proteins involved in the generation, propagation or restoration of electric potentials. The expression of the Na+, K+-ATPase subunit isoforms (alpha, beta and gamma) was studied in dorsal root ganglion (DRG) and sciatic nerve of the rat in normal conditions, after axotomy and during regeneration. In normal DRG, alpha1 and alpha2 are expressed in the plasma membrane of all cell types, while there is no detectable signal for alpha3 in most DRG cells. After axotomy, alpha1 and alpha2 expression decreases evenly in all cells, while there is a remarkable onset in alpha3 expression, with a peak about day 3, which gradually disappears throughout regeneration (day 7). beta1 Is restricted to the nuclear envelope and plasma membrane of neurons and satellite cells. Immediately after injury, beta1 shows a homogeneous distribution in the soma of neurons. No beta2 expression was found. Beta3 Specific immunofluorescence appears in all neurons, although it is brightest in the smallest, diminishing progressively after injury until day 3 and, thereafter, increasing in intensity, until it reaches normal levels. FXYD7 is expressed weakly in a few DRG neurons (less than 2%) and Schwann cells. It increases intensely in satellite cells immediately after axotomy, and in all cell types at day 3. Transient switching of members of the Na+, K+-ATPase isoform family elicited by axotomy suggests variations in the sodium pump isozymes with different affinities for Na+, K+ and ATP from those in intact nerve. This adaptation may be important for regeneration.

Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis.

Despite the recognition that degenerative cartilage disorders like osteoarthritis (OA) and osteochondritis dissecans (OCD) may have nutritional abnormalities at the root of their pathogenesis, balanced dietary supplementation programs have played a secondary role in their management. This review emphasizes the importance and role of nutritional factors such as glucose and glucose-derived sugars (i.e. glucosamine sulfate and vitamin C) in the development, maintenance, repair, and remodeling of cartilage. Chondrocytes, the cells of cartilage, consume glucose as a primary substrate for ATP production in glycolysis and utilize glucosamine sulfate and other sulfated sugars as structural components for extracellular matrix synthesis and are dependent on hexose uptake and delivery to metabolic and biosynthetic pools. Data from several laboratories suggests that chondrocytes express multiple isoforms of the GLUT/SLC2A family of glucose/polyol transporters. These facilitative glucose transporter proteins are expressed in a tissue and cell-specific manner, exhibit distinct kinetic properties, and are developmentally regulated. They may also be regulated by endocrine factors like insulin and insulin-like growth factor I (IGF-I) and cytokines such as interleukin 1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF-alpha). Recent studies suggest that degeneration of cartilage may be triggered by metabolic disorders of glucose balance and that OA occurs coincident with metabolic disease, endocrine dysfunction and diabetes mellitus. Based on these metabolic, endocrine and developmental considerations we present a novel hypothesis regarding the role of glucose transport and metabolism in cartilage physiology and pathophysiology and speculate that supplementation with sugar-derived vitamins and nutraceuticals may benefit patients with degenerative joint disorders.

[The search for new autoantigens in Sjögren's syndrome]. / Búsqueda de nuevos autoantígenos en el síndrome de Sjögren.

OBJECTIVE: To identify new autoantigens related to Sjögren's syndrome and to determine their prevalence in patients and healthy individuals. MATERIAL AND METHODS: Serological sampling was performed in a patient with Sjögren's syndrome through the use of a human brain expression genotec (SEREX technique) to determine expression of known autoantigens and previously undescribed proteins. The presence of a previously unknown protein was found. Several proteins were obtained and two were selected to be studied (a human protein called Tau and an unknown protein described by our group and named hlscA). Both Tau and hIscA cDNA were transformed into an expression plasmid to obtain their recombinant proteins. RESULTS: Using a Western-blot technique we investigated the presence of anti-Tau and anti-hlscA autoantibodies in the sera of 19 patients with Sjögren's syndrome and in the sera of 20 controls. No statistically significant differences were found in the expression of anti-Tau antibodies between patients with Sjögren's syndrome and controls but values of anti-hlscA autoantibodies were significantly lower in patients with Sjögren's syndrome. CONCLUSION: We identified Tau and hIscA proteins as new autoantigens in Sjögren's syndrome. Anti-hlscA antibody values were significantly lower in patients with Sjögren's syndrome than in healthy controls. Although no statistically significant differences in values of anti-Tau antibodies were found between Sjögren's syndrome patients and controls, this is the first time antibodies against this protein have been detected in Sjögren's syndrome.

Búsqueda de nuevos autoantígenos en el síndrome de Sjögren / The search for new autoantigens in Sjögren’s syndrome

Objetivo: Determinar la existencia de nuevos autoantígenos en el síndrome de Sjögren (SS) así como estudiar la prevalencia de éstos en pacientes y población sana. Material y métodos: Se procedió a realizar un muestreo con el suero de una enferma afectada de SS mediante la utilización de una genoteca de cerebro humano (técnica SEREX). Se determinó que este suero expresaba autoantígenos ya conocidos y proteínas no descritas previamente, y también se confirmó la presencia de una proteína desconocida hasta ahora. De entre ellas, se seleccionó a esta última (hIscA) y a la proteína Tau (hallada en el muestreo) para ser transformadas en sendos plásmidos de expresión para conseguir su síntesis recombinante. Resultados: Mediante técnica de inmunotransferencia se testó la existencia de anticuerpos anti-Tau y anti-hIscA en 19 pacientes y 20 sujetos sanos. No se encontró diferencia estadísticamente significativa entre pacientes y controles en la expresión de anticuerpos anti-Tau y se halló que los pacientes expresaban, de forma significativa, valores inferiores de anticuerpos anti-hIscA. Conclusión: Se ha identificado a las proteínas Tau y hIscA como nuevos autoantígenos en el SS. Se ha hallado que los pacientes con SS expresan valores inferiores de anticuerpos anti-hIscA en comparación con controles y, aunque no se ha encontrado ninguna diferencia entre sanos y enfermos en relación con la presencia de anticuerpos anti-Tau, ésta es la primera vez en que anticuerpos contra esta proteína se han detectado en el SS(AU)

Objective: To identify new autoantigens related to Sjögren’s syndrome and to determine their prevalence in patients and healthy individuals. Material and methods: Serological sampling was performed in a patient with Sjögren’s syndrome through the use of a human brain expression genotec (SEREX technique) to determine expression of known autoantigens and previously undescribed proteins. The presence of a previously unknown protein was found. Several proteins were obtained and two were selected to be studied (a human protein called Tau and an unknown protein described by our group and named hlscA). Both Tau and hIscA cDNA were transformed into an expression plasmid to obtain their recombinant proteins. Results: Using a Western-blot technique we investigated the presence of anti-Tau and anti-hlscA autoantibodies in the sera of 19 patients with Sjögren’s syndrome and in the sera of 20 controls. No statistically significant differences were found in the expression of anti-Tau antibodies between patients with Sjögren’s syndrome and controls but values of anti-hlscA autoantibodies were significantly lower in patients with Sjögren’s syndrome. Conclusion: We identified Tau and hIscA proteins as new autoantigens in Sjögren’s syndrome. Anti-hlscA antibody values were significantly lower in patients with Sjögren’s syndrome than in healthy controls. Although no statistically significant differences in values of anti-Tau antibodies were found between Sjögren’s syndrome patients and controls, this is the first time antibodies against this protein have been detected in Sjögren’s síndrome(AU)