ABSTRACT
Chronic myeloid leukemia (CML), a hematopoietic neoplasm arising from the fusion of BCR (breakpoint cluster region) gene on chromosome 22 to the ABL (Abelson leukemia virus) gene on chromosome 9 (BCR-ABL1 oncogene), originates from a small population of leukemic stem cells with extensive capacity for self-renewal and an inflammatory microenvironment. Currently, CML treatment is based on tyrosine kinase inhibitors (TKIs). However, allogeneic hematopoietic stem cell transplantation (HSCT-allo) is currently the only effective treatment of CML. The difficulty of finding a compatible donor and high rates of morbidity and mortality limit transplantation treatment. Despite the safety and efficacy of TKIs, patients can develop resistance. Thus, microRNAs (miRNAs) play a prominent role as biomarkers and post-transcriptional regulators of gene expression. The aim of this study was to analyze the miRNA profile in CML patients who achieved cytogenetic remission after treatment with both HSCT-allo and TKI. Expression analyses of the 758 miRNAs were performed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Bioinformatics tools were used for data analysis. We detected miRNA profiles using their possible target genes and target pathways. MiR-125a-3p stood out among the downregulated miRNAs, showing an interaction network with 52 target genes. MiR-320b was the only upregulated miRNA, with an interaction network of 26 genes. The results are expected to aid future studies of miRNAs, residual leukemic cells, and prognosis in CML.
Subject(s)
Antineoplastic Agents/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , MicroRNAs/metabolism , Adult , Computational Biology , Down-Regulation/drug effects , Female , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Male , MicroRNAs/genetics , Middle Aged , Protein Interaction Maps/drug effects , Up-Regulation/drug effectsABSTRACT
Chronic myeloid leukemia (CML) results from a translocation between chromosomes 9 and 22, which generates the Philadelphia chromosome. This forms BCR/ABL1, an active tyrosine kinase protein that promotes cell growth and replication. Despite great progress in CML treatment in the form of tyrosine kinase inhibitors, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) is currently used as an important treatment alternative for patients resistant to these inhibitors. Studies have shown that unregulated expression of microRNAs, which act as oncogenes or tumor suppressors, is associated with human cancers. This contributes to tumor formation and development by stimulating proliferation, angiogenesis, and invasion. Research has demonstrated the potential of microRNAs as biomarkers for cancer diagnosis, prognosis, and therapeutic targets. In the present study, we compared the circulating microRNA expression profiles of 14 newly diagnosed patients with chronic phase-CML and 14 Philadelphia chromosome-negative patients after allo-HSCT. For each patient, we tested 758 microRNAs by reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis. The global expression profile of microRNAs revealed 16 upregulated and 30 downregulated microRNAs. Target genes were analyzed, and key pathways were extracted and compared. Bioinformatics tools were used to analyze data. Among the downregulated miRNA target genes, some genes related to cell proliferation pathways were identified. These results reveal the comprehensive microRNA profile of CML patients and the main pathways related to the target genes of these miRNAs in cytogenetic remission after allo-HSCT. These results provide new resources for exploring stem cell transplantation-based CML treatment strategies.
ABSTRACT
Chronic myeloid leukemia (CML) is a stem cell derived malignant disorder result of translocation t(9;22)(q34;q11) called Philadelphia chromosome (Ph+). microRNAS (miRNAs) are involved in several biological processes, altering the progression of various pathologies, including CML. This study evaluated whether circulating miRNAs display differential expression profiles in peripheral blood of CML-Chronic Phase (CML-CP) patients newly diagnosed in comparison with CML-CP treated with imatinib. We obtained peripheral blood samples from CML-CP Ph+ patients divided among group 1 (untreated newly diagnosed) and group 2 (treated with imatinib). A pool of total leukocytes from healthy donors was considered as control group. Expression analyses were performed for 768 miRNAs by RT-qPCR array. Bioinformatic tools were used to identify significant pathways and interaction networks. We found 80 deregulated miRNAs between the groups and, according to bioinformatic analysis, they are involved in different pathways, including molecular mechanisms of cancer. The study allows better understanding of disease molecular behavior, and it is useful for possible monitoring CML treatment and prognostic biomarkers identification.
Subject(s)
Biomarkers, Tumor , Circulating MicroRNA , Imatinib Mesylate/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Leukemia, Myeloid, Chronic-Phase/genetics , Protein Kinase Inhibitors/therapeutic use , Transcriptome , Computational Biology/methods , Gene Expression Profiling , Gene Expression Regulation, Leukemic , Humans , Imatinib Mesylate/administration & dosage , Imatinib Mesylate/adverse effects , Leukemia, Myeloid, Chronic-Phase/blood , Leukemia, Myeloid, Chronic-Phase/diagnosis , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effectsABSTRACT
Foram estudados, sob aspectos cito´genético, os cariótipos de sangue periférico de 100 casais com história de abortamentos espontâneos recorrentes, para se investigar a presença de rearranjos cromossômicos. Os resultados mostraram que a frequência total de alterações cromossômicas foi, aproximadamente, 5 por cento, envolvendo translocações equilibradas e inversões. As idades maternas e paternas variaram de 18 a 44 anos e de 18 a 50 anos, respectivamente. A idade gestacional mais frequente na qual ocorreu a perda fetal foi em torno da 10 semana
Subject(s)
Humans , Male , Female , Adolescent , Adult , Abortion, Habitual , Genetic Counseling , Cytogenetic Analysis , KaryotypingABSTRACT
As anomalias cromossômicas estão entre as causas mais comuns de abortamento espontâneo. Aproximadamente 50 por cento das perdas fetais no primeiro trimestre de gestações clinicamente reconhecidas apresentam cariótipos anormais. No segundo trimestre, a frequência é menor, mas ainda considerada importante. Os resultados desse estudo foram obtidos a partir de análise citogenética em 120 amostras de abortamentos espontâneos (vilosidades coriônicas) em primeiro trimestre de gestação. Envolveu uma casuística de 752 mulheres sendo que, 148 haviam apresentado pelo menos uma perda fetal, 35 pelo menos duas e 14 três ou mais. Anomalias cromossômicas foram detectadas em 46,9 por cento das amostras estudadas. O risco de recorrência foi estimado em 23,6 por cento para o segundo aborto e 40 por cento para o terceiro. Observou-se aumento da frequência de produtos de abortamentos com cariótipos alterados em mulheres com idade superior aos 35 anos, isso mostra a relevância do aconselhamento genético para esse grupo e indica a presença de outros fatores na etiologia dos abortamentos de mulheres com idade inferior aos 35 anos, que inclusive apresentaram maior recorrência de abortamentos
