Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Stem Cell Transplantation , Adolescent , Adult , Benzamides , Child , Combined Modality Therapy , Female , Genes, abl , Humans , Imatinib Mesylate , Lymphocyte Transfusion , Male , Middle Aged , Recurrence , Time Factors , Transplantation Chimera , Transplantation, Homologous , Young AdultABSTRACT
BACKGROUND: Expression of the pro-apoptotic BCL-2-interacting mediator (BIM) has recently been implicated in imatinib-induced apoptosis of BCR-ABL1(+) cells. However, the mechanisms involved in the regulation of BIM in CML and its role in the clinical setting have not been established. DESIGN AND METHODS: We analysed the mRNA expression of BIM in 100 newly diagnosed patients with CML in chronic phase by Q-RT-PCR and the protein levels by Western blot analysis. Methylation status was analysed by bisulphite genomic sequencing and MSP. CML cell lines were treated with imatinib and 5-aza-2'-deoxycytidine, and were transfected with two different siRNAs against BIM and cell proliferation and apoptosis were analysed. RESULTS: We demonstrated that down-regulation of BIM expression was present in 36% of the patients and was significantly associated with a lack of optimal response to imatinib as indicated by the decrease in cytogenetic and molecular responses at 6, 12 and 18 months in comparison with patients with normal BIM expression (p<0.05). Expression of BIM was mediated by promoter hypermethylation as demonstrated by restoration of BIM expression after treatment of CML cells with 5-aza-2'-deoxycytidine. Using CML cell lines with low and normal expression of BIM we further demonstrated that the expression of BIM is required for imatinib-induced CML apoptosis. CONCLUSION: Our data indicate that down-regulation of BIM is epigenetically controlled by methylation in a percentage of CML patients and has an unfavourable prognostic impact, and that the combination of imatinib with a de-methylating agent may result in improved responses in patients with decreased expression of BIM.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis Regulatory Proteins/biosynthesis , Down-Regulation/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Membrane Proteins/biosynthesis , Piperazines/pharmacology , Proto-Oncogene Proteins/biosynthesis , Pyrimidines/pharmacology , Adult , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Apoptosis Regulatory Proteins/genetics , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Bcl-2-Like Protein 11 , Benzamides , Cell Proliferation/drug effects , DNA Methylation , DNA Modification Methylases/antagonists & inhibitors , Decitabine , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Drug Evaluation, Preclinical/methods , Drug Resistance, Neoplasm/genetics , Epigenesis, Genetic , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Expression Regulation, Neoplastic/genetics , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Membrane Proteins/genetics , Middle Aged , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins/genetics , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Tumor Cells, CulturedABSTRACT
PURPOSE: To identify microRNAs (miRNAs) epigenetically regulated in acute lymphoblastic leukemia (ALL). METHODS: We first examined ALL-derived cell lines for the presence of abnormal levels of two different histone modifications (trimethylation of H3 lysine 4 [K4H3me3] and dimethylation of H3 lysine 9 [K9H3me2]) in the 5'UTR regions around CpG islands of 78 miRNAs by chromatin immunoprecipitation (ChIP)-on-ChIP analysis. Methylation status (methylation-specific polymerase chain reaction [PCR]) and expression (quantitative PCR) of miRNAs showing a pattern of histone modifications linked to a closed chromatin structure were analyzed in a panel of six ALL cell lines and in 353 ALL patients. RESULTS: CpG islands around 13 miRNAs disclosed high levels of K9H3me2 and/or low levels of K4H3me3, a pattern of histone modifications underlying a closed chromatin structure associated with repressive gene expression. Complete consistency in the correlation between both histone marks, the presence of DNA methylation around these miRNAs, and their expression patterns was confirmed in the six ALL cell lines. Treatment with 5-Aza-2'-deoxycytidine upregulated the expression levels of these genes, suggesting that epigenetic mechanisms deregulate the expression of these miRNAs. A total of 65% of the ALL samples had at least one miRNA methylated (methylated group). Estimated disease-free survival (DFS) and overall survival (OS) at 14 years were 78% and 71% for nonmethylated patients and 24% and 28% for methylated patients (P = .00001 for both). Multivariate analysis demonstrated that methylation profile was an independent prognostic factor for predicting DFS (P = .0001) and OS (P = .0001). CONCLUSION: Aberrant miRNA methylation is a common phenomenon in ALL that affects the clinical outcome of these patients.
Subject(s)
Epigenesis, Genetic , MicroRNAs/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Cell Line, Tumor , CpG Islands , DNA Methylation , Female , Humans , Male , Middle Aged , Multivariate Analysis , PrognosisABSTRACT
La hidradenitis ecrina neutrofílica (HEN) es una dermatosis inflamatoria poco frecuente y autolimitada, caracterizada por un infiltrado neutrofílico alrededor de las glándulas ecrinas y que se presenta clínicamente con diferentes tipos de lesiones. La HEN ocurre con más frecuencia en pacientes tras recibir quimioterapia por neoplasias hematológicas. Se presenta un caso de HEN en un paciente neutropénico varón de 70 años que recibió tioguanina por una leucemia aguda mieloide. Las placas eritematosas desaparecieron en 3-4 semanas. Los hallazgos histológicos fueron compatibles con HEN. Los cultivos cutáneos excluyeron causas infecciosas
Neutrophilic eccrine hidradenitis (NEH) is an infrequent, self-limited inflammatory dermatosis characterized by a neutrophilic infiltrate around the eccrine glands. Clinically, it presents with different types of lesions. NEH occurs most frequently in patients who have undergone chemotherapy for hematologic neoplasms. We present a case of NEH in a 70-year-old neutropenic male who received thioguanine for acute myeloid leukemia. The erythematous plaques disappeared in 3-4 weeks. The histological findings were compatible with NEH. Skin cultures ruled out infectious causes
Subject(s)
Male , Middle Aged , Humans , Hidradenitis/diagnosis , Hidradenitis/therapy , Neutropenia/complications , Prednisone/therapeutic use , Thioguanine/adverse effects , Thioguanine/therapeutic use , Recurrence , Hematologic Neoplasms/complications , Hematologic Neoplasms/drug therapy , Hidradenitis/drug therapy , Skin Diseases/diagnosis , Skin Diseases/therapy , Burkitt Lymphoma/complicationsABSTRACT
Neutrophilic eccrine hidradenitis (NEH) is an infrequent, self-limited inflammatory dermatosis characterized by a neutrophilic infiltrate around the eccrine glands. Clinically, it presents with different types of lesions. NEH occurs most frequently in patients who have undergone chemotherapy for hematologic neoplasms. We present a case of NEH in a 70-year-old neutropenic male who received thioguanine for acute myeloid leukemia. The erythematous plaques disappeared in 3-4 weeks. The histological findings were compatible with NEH. Skin cultures ruled out infectious causes.
