The possibility of early diagnosis of colorectal cancer through expression of Lncrna UCA1, Lncrna LINC00970, and Wnt genes; an in-vitro study

Colorectal cancer is the 4thcause of cancer death; with considering the growth process of this cancer and the necessity of early diagnosis, the purpose of the research is to state the LncRNA 00970, LncRNA UCAI,and the Wntgene before and after the treatment by 5-Azacytidine epigenetic medicine, to reach the biomarker in the very first steps of colorectal cancer. In this experiment, the human colon cancer cell line (HT29) treated with different concentrations of 5-aza-2'-deoxycytidine (5-aza-dC) was utilized to induce DNA demethylation; Quantitative PCR (qPCR) was used to measure LncRNA UCA1and LncRNA LINC00970 and Wntexpression. There was a significant relationship between the expression of LncRNA 00970, LncRNA UCAI,and the Wntgene and its effects on colorectal (p < 0.05). The Wntgene was treated by 1 and 10 of 5-Azacytidine epigenetic medicine, which then experienced decreases. In LncRNA UCAI and LncRNA00970 in dose 1 micromolar of 5-Azacytidine had decrement and increment of expressionrespectively that explains their efficiency but in treatment by dose 10 mM of this medicine, no significant LncRNA expression difference was detected, 5-azacitidine has a direct impact on its target genes and LncRNAs.Therefore, it can be used in the early diagnosis of colorectal cancer.

SOHO State of the Art Updates and Next Questions: The Past, Present and Future of Venetoclax-Based Therapies in AML.

The use of venetoclax in combination with hypomethylating agents (HMA) has changed the paradigm for the treatment of acute myeloid leukemia (AML) in elderly patients and those unfit for intensive chemotherapy. A phase 3 study has shown superior response rates and improved overall survival for patients treated with venetoclax + azacitidine compared with the previous standard of care, azacitidine alone. This success has led to multiple exciting follow-up studies, including investigations related to the discovery of predictors of response, relapse, and the mechanism of action of this therapy. While venetoclax + HMA has shown significant benefit in elderly patients unfit for chemotherapy, further questions remain as to how this therapy can be expanded into other populations including relapsed or refractory patients and younger newly diagnosed patients with adverse risk features. In this article, we discuss the clinical outcomes of AML with venetoclax + HMA, established and potential predictors of response to this regimen, its mechanisms of action, and speculate on the future of venetoclax + HMA therapy in AML.

Transitory response of a myelodysplastic syndrome with deletion of chromosome 5q to thalidomide. Report of one case

ABSTRACT Myelodysplastic syndrome with deletion of chromosome 5q (5q-syndrome) has a favorable prognosis and a low risk of transformation to acute myeloid leukemia, when treated with lenalidomide. Azacitidine leads to complete remission even as second-line therapy and in patients with clonal evolution. We report a 70 years old female without previous exposure to myelotoxic drugs, presenting with three weeks with fatigue and dyspnea. She had anemia with normal white blood cell and platelet count. Bone marrow biopsy showed 50% cellularity and the karyotype analysis revealed a (5) (q33q34) deletion in 22% of the metaphases. A diagnosis of 5q-syndrome with low risk calculated using the Revised International Prognostic Scoring System (IPSS-R), was made. Since lenalidomide was not affordable, thalidomide 100 mg/day was initiated, achieving transfusion independence for three years. Afterwards, she developed pancytopenia and a bone marrow biopsy showed erythroid and megakaryocyte dysplasia with a complex karyotype, which worsened prognosis (IPSS-R of five points). Therefore, azacitidine (by donation) was administered. She achieved complete remission with a normal karyotype and completed 12 cycles of treatment. Thereafter, she relapsed and received only supportive care for a year. She suffered an ischemic stroke and died two weeks later.

El síndrome mielodisplásico con deleción del cromosoma 5q (síndrome 5q) tiene un pronóstico favorable y riesgo bajo de transformación a leucemia aguda en pacientes que son tratados con lenalidomida (tratamiento estándar). El uso Azactidina tiene respuestas completas incluso como segunda línea de tratamiento en pacientes con evolución clonal. Presentamos una mujer de 71 años, sin exposición a mielotóxicos que debutó con un síndrome anémico. Se realizó biopsia de medula ósea que mostró celularidad del 50% y en el análisis citogenético se detectó una deleción del cromosoma 5 en 22% de las metafases analizadas, lo que llevó al diagnóstico de Síndrome 5q- de riesgo bajo de acuerdo con el puntaje IPSS-R (Revised International Prognostic Scoring System). Ya que no se pudo costear lenalidomida, se trató con talidomida (100 mg/día). Permaneció tres años sin requerir soporte transfusional. Posteriormente, presentó pancitopenia y en el nuevo aspirado de médula ósea se observó displasia de la serie roja y megacariocitos, con cariotipo complejo y peor pronóstico (IPSS-R 5 puntos). Se trató con 12 ciclos de azacitidina con lo que logró respuesta completa. Recayó 12 meses después y continuó manejo de soporte por un año. Finalmente falleció debido a un accidente vascular cerebral.

BRD4 Inhibition Enhances Azacitidine Efficacy in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell-based disorders characterized by ineffective hematopoiesis, increased genomic instability and a tendency to progress toward acute myeloid leukemia (AML). MDS and AML cells present genetic and epigenetic abnormalities and, due to the heterogeneity of these molecular alterations, the current treatment options remain unsatisfactory. Hypomethylating agents (HMA), especially azacitidine, are the mainstay of treatment for high-risk MDS patients and HMA are used in treating elderly AML. The aim of this study was to investigate the potential role of the epigenetic reader bromodomain-containing protein-4 (BRD4) in MDS and AML patients. We identified the upregulation of the short variant BRD4 in MDS and AML patients, which was associated with a worse outcome of MDS. Furthermore, the inhibition of BRD4 in vitro with JQ1 or shRNA induced leukemia cell apoptosis, especially when combined to azacitidine, and triggered the activation of the DNA damage response pathway. JQ1 and AZD6738 (a specific ATR inhibitor) also synergized to induce apoptosis in leukemia cells. Our results indicate that the BRD4-dependent transcriptional program is a defective pathway in MDS and AML pathogenesis and its inhibition induces apoptosis of leukemia cells, which is enhanced in combination with HMA or an ATR inhibitor.

Response and survival in acute myeloid leukemia patients not candidates to transplantation treated with azacitidine versus palliative treatment: a retrospective study.

INTRODUCTION: Acute myeloid leukemia has a high mortality if untreated. Hematopoietic stem cell transplantation is the only curative treatment so far. Patients who are not eligible to receive a transplant can be treated with hypomethylating agents that have shown to improve disease-free and overall survival. OBJECTIVE: Retrospective description of the clinical characteristics of patients suffering from advanced myelodysplastic syndrome and acute myeloid leukemia that were treated with a hypomethylating agent as well as its adverse effects and response to treatment. METHODS: This report shows our experience in 38 patients with acute myeloid leukemia treated with azacitidine or palliative treatment. RESULTS: Azacitidine was able to prolong survival in 80% of patients with a high incidence of adverse effects and negative impact on quality of life. Most of the patients treated with palliative intent died in the first month after diagnosis. CONCLUSIONS: Azacitidine can prolong survival but with significant adverse effects. Untreated patients had a high early mortality.

INTRODUCCIÓN : La leucemia mieloide aguda tiene una alta mortalidad sin tratamiento. El trasplante hematopoyético es la única estrategia curativa hasta ahora. Los pacientes que tienen contraindicaciones para el trasplante, pueden ser tratados con fármacos hipometilantes que han mostrado mejorar la sobrevida libre de enfermedad y sobrevida global. OBJETIVOS: Describir las características clínicas de los pacientes con síndrome mielodisplásico avanzado y leucemia mieloide aguda, las respuestas logradas y efectos adversos del tratamiento con el fármaco hipometilante. MÉTODOS: Este reporte muestra nuestra experiencia en 38 pacientes con leucemia mieloide aguda tratados con azacitidina o con tratamiento paliativo. RESULTADOS: La azacitidina permitió alargar la sobrevida en 80% de los pacientes con alta incidencia de efectos adversos y afectación de la calidad de vida. La mayoría de los pacientes tratados con intención paliativa, fallecieron en el primer mes post diagnóstico. CONCLUSIONES: La azacitidina permite prolongar la sobrevida, pero con efectos adversos considerables.

Azacitidine and lenalidomide as an alternative treatment for refractory acute myeloid leukemia: a case report / Azacitidina e lenalidomida como alternativa de tratamento para leucemia mieloide aguda refratária: um relato de caso

CONTEXT: Refractory acute myeloid leukemia (AML) is a difficult disease to control with second or third-line chemotherapy regimens. In this report, we describe using azacitidine in combination with lenalidomide as salvage therapy. CASE REPORT: 52-year-old female was diagnosed with refractory AML and high-risk cytogenetics: complex monosomal karyotype consisting of t (3, 3) in association with monosomy 7 and del 5q. Morphological remission associated with maintenance of the cytogenetic abnormality of chromosome 3 and disappearance of the abnormalities relating to chromosomes 5 and 7 was achieved after three cycles of combination therapy with azacitidine and lenalidomide. CONCLUSION: Azacitidine plus lenalidomide can be a therapeutic option for patients with refractory AML, as illustrated in this case. .

CONTEXTO: A leucemia mieloide aguda (LMA) refratária é considerada doença de difícil controle com regime quimioterápico de segunda ou terceira linha. Neste relato, é descrito o uso de azacitidina em combinação com lenalidomida como esquema de resgate. RELATO DE CASO: Paciente de 52 anos, do sexo feminino, com o diagnóstico de LMA refratária de alto risco citogenético, apresentava cariótipo complexo e monossômico, com t (3, 3), associado à monosomia do 7 e del 5q. Destaca-se que, após três ciclos da terapia combinada com azacitidina e lenalidomida, houve remissão morfológica, com manutenção da anormalidade citogenética relacionada ao cromossomo 3 e desaparecimento da anormalidade relacionada aos cromossomos 5 e 7. CONCLUSÃO: Azacitidina e lenalidomida podem ser opção terapêutica para pacientes com LMA refratária, como demonstrado neste caso. .

Epigenetic therapy in allogeneic hematopoietic stem cell transplantation.

DNA methylation and other epigenetic phenomena appear to be relevant in the pathogenesis of several malignant disorders. DNA methyltransferases add methyl groups to cytosine-phosphate-guanine (CpG) islandsleading to gene promoter silencing. The DNA methyltransferases inhibitors azacitidine and decitabine have anti-tumor activity against a broad range of malignancies, but have been investigated mostly in myelodysplastic syndrome. In addition, these agents have immunomodulatory effects that are under investigation in the allogeneic stem cell transplantation scenario. Both drugs have been used in the perioperative period of allogeneic transplantations with varying degrees of success. It has been hypothesized that low dose azacitidine may increase the graft-versus-leukemia effect and have a role in the maintenance of remission after allogeneic transplantation for myeloid leukemias. It is also intriguing that this favorable effect might occur while mitigating graft-versus-host disease. Here we present a review of the rapidly growing field of epigenetic manipulation using hypomethylating agents in allogeneic transplantation.

Epigenetic therapy in allogeneic hematopoietic stem cell transplantation

DNA methylation and other epigenetic phenomena appear to be relevant in the pathogenesis of several malignant disorders. DNA methyltransferases add methyl groups to cytosine-phosphate-guanine (CpG) islandsleading to gene promoter silencing. The DNA methyltransferases inhibitors azacitidine and decitabine have anti-tumor activity against a broad range of malignancies, but have been investigated mostly in myelodysplastic syndrome. In addition, these agents have immunomodulatory effects that are under investigation in the allogeneic stem cell transplantation scenario. Both drugs have been used in the perioperative period of allogeneic transplantations with varying degrees of success. It has been hypothesized that low dose azacitidine may increase the graftversus-leukemia effect and have a role in the maintenance of remission after allogeneic transplantation for myeloid leukemias. It is also intriguing that this favorable effect might occur while mitigating graft-versus-host disease. Here we present a review of the rapidly growing field of epigenetic manipulation using hypomethylating agents in allogeneic transplantation.

Cytogenetic effect of 5-azacytidine in patients with hematological malignancies

BACKGROUND: Recently, the importance of cytogenetics has grown in the diagnosis, prognosis and treatment of leukemias and myelodysplastic syndromes. 5-azacytidine is a drug that has well-known cytogenetical effects and is approved in the treatment of myelodysplastic syndromes. To date, no studies have been performed to evaluate the impact of 5-azacytidine on the chromosomes of patients with hematological neoplasias. This study aimed to investigate the effects of 5-azacytidine on chromosomes of patients with different hematological malignancies using G-band analyses to identify possible cytogenetical alterations. METHODS: The peripheral blood of 18 patients with hematological malignancies and 18 controls was collected in heparinized tubes. 5-azacytidine was added, at a final concentration of 10-5M, to cultures 7 hours prior to harvest. RESULTS: Uncoiled centromeric/pericentromeric heterochromatin of chromosomes-1, 9 and 16 occurred more frequently in the patients than in controls. This higher frequency of uncoiled heterochromatin was statistically significant (p-value = 0.004) for chromosome-9. Conversely, we observed that the fragile site at 19q13 was more frequent in controls (p-value = 0.0468). CONCLUSIONS: The results of this study suggest that satellite sequences, located in the heterochromatin of chromosome-9, are hypomethylated in hematological malignancies. This hypomethylation may contribute to the disease, activating transposable elements and/or promoting genomic instability, enabling the loss of heterozygosity of important tumor suppressor genes. An investigation of the 19q13 region may help to understand whether or not the predominant occurrence of the fragile site at 19q13 in controls is due to hypermethylation of this region.

Cytogenetic effect of 5-azacytidine in patients with hematological malignancies.

BACKGROUND: Recently, the importance of cytogenetics has grown in the diagnosis, prognosis and treatment of leukemias and myelodysplastic syndromes. 5-azacytidine is a drug that has well-known cytogenetical effects and is approved in the treatment of myelodysplastic syndromes. To date, no studies have been performed to evaluate the impact of 5-azacytidine on the chromosomes of patients with hematological neoplasias. This study aimed to investigate the effects of 5-azacytidine on chromosomes of patients with different hematological malignancies using G-band analyses to identify possible cytogenetical alterations. METHODS: The peripheral blood of 18 patients with hematological malignancies and 18 controls was collected in heparinized tubes. 5-azacytidine was added, at a final concentration of 10-5M, to cultures 7 hours prior to harvest. RESULTS: Uncoiled centromeric/pericentromeric heterochromatin of chromosomes-1, 9 and 16 occurred more frequently in the patients than in controls. This higher frequency of uncoiled heterochromatin was statistically significant (p-value = 0.004) for chromosome-9. Conversely, we observed that the fragile site at 19q13 was more frequent in controls (p-value = 0.0468). CONCLUSIONS: The results of this study suggest that satellite sequences, located in the heterochromatin of chromosome-9, are hypomethylated in hematological malignancies. This hypomethylation may contribute to the disease, activating transposable elements and/or promoting genomic instability, enabling the loss of heterozygosity of important tumor suppressor genes. An investigation of the 19q13 region may help to understand whether or not the predominant occurrence of the fragile site at 19q13 in controls is due to hypermethylation of this region.