RESUMO
OBJECTIVE@#To investigate the cytotoxic effect and its mechanism of the micromolecule compound on the leukemia cells.@*METHODS@#The cytotoxic effects of 28 Nilotinib derivatives on K562, KA, KG, HA and 32D cell lines were detected by MTT assays, and the compound Nilo 22 was screen out. Cell apoptosis and cell cycle on leukemia cells were detected by flow cytometry. The effect of compound screened out on leukemogenesis potential of MLL-AF9 leukemia mice GFP@*RESULTS@#Nilo 22 serves as the most outstanding candidate out of 28 Nilotinib derivatives, which impairs leukemia cell lines, but spares normal hematopoietic cell line. Comparing with Nilotinib, Nilo 22 could induce the apoptosis of GFP@*CONCLUSION@#Nilo 22 shows a significant cytotoxic effect on mice and human leukemia cells, especially for drug resistance cells. Nilo 22 is a promising anti-leukemia agent to solve the common clinical problems of drug resistance and relapse of leukemia.
Assuntos
Animais , Humanos , Camundongos , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Leucemia , Proteína de Leucina Linfoide-Mieloide/genética , Telomerase/metabolismo , Telômero/metabolismoRESUMO
OBJECTIVE@#To explore the genetic basis for a child with unexplained global developmental delay (GDD), seizure, and facial deformity.@*METHODS@#Whole exome sequencing (WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of the patient and his parents.@*RESULTS@#WES revealed that the patient has carried a previously unreported de novo heterozygous nonsense c.4906C>T (p.Arg1636Ter) variant of the KMT2A gene, Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.4906C>T variant of KMT2A gene was predicted to be pathogenic (PVS1+ PS2+ PM2+PP3).@*CONCLUSION@#The heterozygous nonsense c.4906C>T (p.Arg1636Ter) variant of the KMT2A gene probably underlay the disease in the child. Above finding has enriched the spectrum of pathogenic variants of the KMT2A gene.
Assuntos
Criança , Humanos , Masculino , Anormalidades Múltiplas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Proteína de Leucina Linfoide-Mieloide/genética , SíndromeRESUMO
OBJECTIVE@#To investigate the clinical features and prognosis of acute myeloid leukemia (AML) patients with the mixed lineage leukemia (MLL) gene rearrangements AF6 (MLL-AF6) positive.@*METHODS@#In the study, 11 patients who were newly diagnosed with MLL-AF6 positive AML were analyzed retrospectively, related literature was reviewed to clarify the clinical features and prognosis of MLL-AF6 positive patients.@*RESULTS@#Among the 11 patients, there were 6 males and 5 females, with a median age of 36 years. Six patients were diagnosed with AML M5 and five with M4 according to FAB classification (French-American-British classification systems). Gingival swelling and pain occurred in 6 cases and fever occurred in 5 cases. At first diagnosis, the median white blood cells were 55.5×109/L. Immunotype showed the expression of myeloid/monocyte and early stem cell series antigens. The expression level of MLL-AF6 fusion gene (real-time quantitative PCR) was 14.2%-214.5%, and 6/11 cases (54.5%) were associated with high EVI1 gene expression. Mutations of KRAS, TET2, ASXL1, TP53, DNMT3A, and FLT3-ITD were detected by next generation sequencing (NGS) in 4 patients. Chromosome G banding examination showed that 2 cases were t(6;11)(q27, q23) with complex karyotype abnormality, 4 cases with +8 abnormality and 2 cases with normal karyotype. Hematological complete remission (CR) was achieved in 8/11 patients (72.7%) after conventional induction chemotherapy, and primary drug resistance was observed in 3 patients. Two of the eight patients with CR were negative for minimal residual disease (MRD), with a median CR duration of 4.5 months. Two patients with positive MRD and three patients with refractory recurrence underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), but all died due to leukemia progression. At the end of follow-up on December 1, 2019, 2 patients were alive and 9 died, with median survival time of 9 months.@*CONCLUSION@#The AML patients with MLL-AF6 positive were mostly young, the majority of FAB types were M4 and M5, and most of the patients often had fever as the first symptom, with increased white blood cells, accompanied by organ infiltration, and high EVI1 gene expression. The hematological remission rate of routine chemotherapy is not low, but it is difficult to achieve molecular remission, most of which have early recurrence. Early allo-HSCT in a molecular negative state may prolong the CR duration.
Assuntos
Adulto , Feminino , Humanos , Masculino , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Prognóstico , Indução de Remissão , Estudos RetrospectivosRESUMO
OBJECTIVE@#To explore the clinical-biological characteristics and prognosis of pediatric pro-B cell acute lymphoblastic leukemia (pro-B-ALL).@*METHODS@#A total of 64 patients aged less than 18 years old with pro-BALL were enrolled. Clinical characteristics, therapeutic effect and prognostic factors were retrospectively analyzed.@*RESULTS@#Pro-B-ALL occurred in 6.23% (64/1 028) of pediatric ALL. Among the 64 patients, 35 were male and 29 were female. The median age was 7.0 years (range 0.4-16.0 years) at diagnosis, of which 39% and 6% were ≥ 10 years old and < 1 year old respectively. The median WBC count was 25.5×10@*CONCLUSIONS@#Pediatric pro-B ALL is a heterogeneous disease with clinical and biological diversity. Biological characteristics, such as immunological markers, genetic alterations, and MRD at 3 months after chemotherapy may be important factors for the long-term prognosis.
Assuntos
Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Antígenos CD/genética , Intervalo Livre de Doença , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Prognóstico , Estudos RetrospectivosRESUMO
Abstract Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.
Resumen Descripción del caso: Se reporta el caso de una paciente femenina de un año de edad, diagnosticada con Síndrome de Wiedemann-Steiner basado en la identificación de una nueva variante patogénica de novo de tipo frameshift en el gen KMT2A Mediante secuenciación de exoma usando el enfoque de trio, sumado a sus características clínicas. Hallazgos clínicos: las mutaciones en KMT2A causan el Síndrome de Wiedemann-Steiner, un desorden genético muy raro caracterizado por hipertricosis congénita, talla baja, retardo mental variable y fenotipo facial distintivo, los cuales se encuentran en la paciente reportada. Resultado: La Secuenciación de exoma completo encontró una variante de tipo frameshift: c.4177dupA (p. Ile1393Asnfs * 14) en KMT2A, este cambio a nivel génico genera una alteración de la unión específica a motivos CpG no metilados del DNA a la proteína. El genotipo y el fenotipo de la paciente fue comparado con los pacientes reportados previamente en la literatura. Relevancia clínica: En enfermedades con baja frecuencia como la aquí reportada es necesario establecer correlaciones genotipo-fenotipo que permitan establecer planes terapéuticos y de seguimiento. El análisis realizado no evidenció diferencias atribuibles a sexo o edad entre los pacientes diagnosticados con Síndrome de Weidemann-Steiner. La secuenciación de exoma permitió identificar causalidad en este caso, cuya característica principal de hipertricosis se asocia con alta heterogeneidad clínica y genética.
Assuntos
Feminino , Humanos , Lactente , Anormalidades Múltiplas/diagnóstico , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Hipertricose/congênito , Deficiência Intelectual/genética , Fenótipo , Síndrome , Anormalidades Múltiplas/genética , Genótipo , Hipertricose/genética , MutaçãoRESUMO
No abstract available.
Assuntos
Feminino , Humanos , Masculino , Adulto Jovem , Sequência de Bases , Proteínas de Ciclo Celular/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 22 , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Imunofenotipagem , Hibridização in Situ Fluorescente , Cariótipo , Leucemia Mieloide Aguda/diagnóstico , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Septinas/genética , Análise de Sequência de DNA , Translocação GenéticaRESUMO
No abstract available.
Assuntos
Adolescente , Humanos , Masculino , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 4 , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genéticaRESUMO
No abstract available.
Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antígenos CD4/metabolismo , Antígeno CD56/metabolismo , Medula Óssea/metabolismo , Células Dendríticas/citologia , Erros de Diagnóstico , Éxons , Citometria de Fluxo , Rearranjo Gênico , Neoplasias Hematológicas/diagnóstico , Histona-Lisina N-Metiltransferase/genética , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/diagnóstico , Proteína de Leucina Linfoide-Mieloide/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Fatores de Transcrição/genética , Translocação GenéticaRESUMO
Objective: Peritraumatic reactions feature prominently among the main predictors for development of posttraumatic stress disorder (PTSD). Peritraumatic tonic immobility (PTI), a less investigated but equally important type of peritraumatic response, has been recently attracting the attention of researchers and clinicians for its close association with traumatic reactions and PTSD. Our objective was to investigate the role of PTI, peritraumatic panic, and dissociation as predictors of PTSD symptoms in a cohort of police recruits (n=132). Methods: Participants were asked to complete the following questionnaires during academy training and after the first year of work: Posttraumatic Stress Disorder Checklist - Civilian Version (PCL-C), Physical Reactions Subscale (PRS), Peritraumatic Dissociative Experiences Questionnaire (PDEQ), Tonic Immobility Scale (TIS), and Critical Incident History Questionnaire. Results: Employing a zero-inflated negative binomial regression model, we found that each additional point in the TIS was associated with a 9% increment in PCL-C mean scores (RM = 1.09), whereas for PRS, the increment was 7% (RM = 1.07). As the severity of peritraumatic dissociation increased one point in the PDEQ, the chance of having at least one symptom in the PCL-C increased 22% (OR = 1.22). Conclusions: Our findings highlight the need to expand investigation on the incidence and impact of PTI on the mental health of police officers. .
Assuntos
Animais , Humanos , Camundongos , Proteínas Cromossômicas não Histona/fisiologia , Leucemia/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Células-Tronco Neoplásicas/patologia , Oncogenes , Proteínas Repressoras/fisiologia , Apoptose , Proteínas Cromossômicas não Histona/genética , Citometria de Fluxo , Leucemia/genética , Leucemia/metabolismo , Reação em Cadeia da Polimerase , Proteínas Repressoras/genéticaRESUMO
No abstract available.
Assuntos
Idoso , Criança , Feminino , Humanos , Lactente , Masculino , Linfócitos B/citologia , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 9 , Imunofenotipagem , Cariotipagem , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Translocação GenéticaRESUMO
Rearrangements of the mixed lineage leukemia (MLL) gene at 11q23 commonly occur in infants with CALLA negative B lymphoblastic leukemia (B-ALL). Most often, these are detected by conventional karyotyping; however, fluorescent in-situ hybridization (FISH) with the help of a dual-color break-apart probe is used to identify cryptic translocations. When there is an MLL gene translocations the usual FISH signal pattern is 1 red-1 yellow fusion signal pattern We present a case of an infant with CALLA negative precursor B-ALL with a characteristic translocations t(4;11) (q21;q23),however,with an unusual MLL FISH signal pattern.
Assuntos
Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Masculino , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Translocação GenéticaRESUMO
The chromosome band 11q23 is a common target region of chromosomal translocation in different types of leukemia, including infantile leukemia and therapy-related leukemia. The target gene at 11q23, MLL, is disrupted by the translocation and becomes fused to various translocation partners. We report a case of AML with a rare 3-way translocation involving chromosomes 1, 9, and 11: t(1;9;11)(p34.2;p22;q23). A 3-yr-old Korean girl presented with a 5-day history of fever. A diagnosis of AML was made on the basis of the morphological evaluation and immunophenotyping of bone marrow specimens. Flow cytometric immunophenotyping showed blasts positive for myeloid lineage markers and aberrant CD19 expression. Karyotypic analysis showed 46,XX,t(1;9;11)(p34.2;p22;q23) in 19 of the 20 cells analyzed. This abnormality was involved in MLL/MLLT3 rearrangement, which was confirmed by qualitative multiplex reverse transcription-PCR and interphase FISH. She achieved morphological and cytogenetic remission after 1 month of chemotherapy and remained event-free for 6 months. Four cases of t(1;9;11)(v;p22;q23) have been reported previously in a series that included cases with other 11q23 abnormalities, making it difficult to determine the distinctive clinical features associated with this abnormality. To our knowledge, this is the first description of t(1;9;11) with clinical and laboratory data, including the data for the involved genes, MLL/MLLT3.
Assuntos
Pré-Escolar , Feminino , Humanos , Antígenos CD19/metabolismo , Células da Medula Óssea/patologia , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 9 , Imunofenotipagem , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Mieloide Aguda/diagnóstico , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/genética , Translocação GenéticaRESUMO
This study investigated the spectrum of chromosomal abnormalities in 325 leukemia patients and developed optimal profiles of leukemic fusion genes for multiplex RT-PCR. We prospectively analyzed blood and bone marrow specimens of patients with acute leukemia. Twenty types of chromosomal abnormalities were detected in 42% from all patients by commercially available multiplex RT-PCR for detecting 28 fusion genes and in 35% by cytogenetic analysis including FISH analysis. The most common cytogenetic aberrations in acute myeloid leukemia patients was PML/PARA, followed by AML1/MGT8 and MLL1, and in acute lymphoid leukemia patients was BCR/ABL, followed by TEL/AML1 and MLL1 gene rearrangement. Among the negative results for multiplex RT-PCR, clinically significant t(3;3)(q21;q26.2), t(8;14)(q24;q32) and i(17)(q10) were detected by conventional cytogenetics. The spectrum and frequency of chromosomal abnormalities in our leukemia patients are differed from previous studies, and may offer optimal profiles of leukemic fusion genes for the development of new molecular detection systems.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Adaptadoras de Transdução de Sinal/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 8 , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Fusão bcr-abl/genética , Rearranjo Gênico , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Therapy-related ALL (t-ALL) is a rare secondary leukemia that develops after chemotherapy and/or radiotherapy for primary malignancies. Chromosomal 11q23 abnormalities are the most common karyotypic alterations in t-ALL. The t(11;19)(q23;p13) aberration is extremely rare and has not been confirmed at the molecular genetic level. Here, we report a case of t-ALL with t(11;19)(q23;p13.3) and MLL-MLLT1 (alias ENL) gene rearrangement confirmed by cytogenetic analysis, multiplex reverse transcription-PCR (multiplex RT-PCR), and DNA sequencing in a patient who had undergone treatment for breast cancer. A 40-yr-old woman developed acute leukemia 15 months after undergoing 6 cycles of adjuvant chemotherapy (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2), radiation therapy (dose, 5,900 cGy), and anticancer endocrine therapy with tamoxifen. The complete blood cell counts and bone marrow examination showed increased blasts and the blasts showed B lineage immunophenotype (positive for CD19, CD34, and cytoplasmic CD79a). Cytogenetic analysis revealed the karyotype 47,XX,+X,t(11;19)(q23;p13.3)[4]/46,XX[16]. FISH analyses, multiplex RT-PCR, and DNA sequencing confirmed the MLL-MLLT1 gene rearrangement. The patient underwent induction chemotherapy with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) and achieved complete remission. Subsequently, she underwent consolidation chemotherapy, but died of brain ischemia in the pons and the region of the middle cerebral artery. To our knowledge, this is the first case report of t-ALL with t(11;19)(q23;p13.3) and the MLL-MLLT1 gene rearrangement.
Assuntos
Adulto , Feminino , Humanos , Antineoplásicos/uso terapêutico , Sequência de Bases , Neoplasias da Mama/tratamento farmacológico , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 19 , Terapia Combinada , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Rearranjo Gênico , Imunofenotipagem , Cariotipagem , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Análise de Sequência de DNA , Tamoxifeno/uso terapêutico , Fatores de Transcrição/genética , Translocação GenéticaRESUMO
ALL with MLL gene rearrangement secondary to chemotherapy has been rarely reported. We report a case of therapy-related ALL (t-ALL) with MLL gene rearrangement in a patient who had undergone treatment for breast cancer. A 60-yr-old woman with breast cancer underwent breast-conserving surgery followed by 6 cycles of adjuvant chemotherapy (cyclophosphamide, epirubicin, and fluorouracil) and radiation therapy (dose, 5,040 cGy to the left breast and a 1,000 cGy boost to the tumor bed). A follow-up examination performed 14 months after the chemotherapy revealed no evidence of breast malignancy. However, the patient's complete blood cell count indicated acute leukemia: white blood cell count, 174.1x10(9)/L with 88% blasts; Hb level, 12.5 g/dL; and platelet count, 103.0x10(9)/L. Examination of the bone marrow aspirate smear revealed a high percentage of blasts (85.1% of all nucleated cells); the blasts showed a pro-B immunophenotype and were positive for CD19, CD79a, HLA-DR, CD34, and terminal deoxynucleotidyl transferase (TdT). Cytogenetic and FISH analyses revealed t(4;11)(q21;q23) and MLL gene rearrangement, respectively. The patient received induction chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone and achieved complete remission. Following consolidation chemotherapy, she underwent allogenic peripheral blood stem cell transplantation and has been clinically stable. To our knowledge, this is the first reported case of t-ALL with MLL gene rearrangement following treatment of breast cancer in Korea.
Assuntos
Feminino , Humanos , Antibióticos Antineoplásicos/uso terapêutico , Contagem de Células Sanguíneas , Medula Óssea/patologia , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Terapia Combinada , Ciclofosfamida/uso terapêutico , Análise Citogenética , Epirubicina/uso terapêutico , Fluoruracila/uso terapêutico , Rearranjo Gênico , Transplante de Células-Tronco Hematopoéticas , Hibridização in Situ Fluorescente , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Translocação GenéticaRESUMO
Topoisomerase II inhibitors are effective chemotherapeutic agents in the treatment of cancer, in spite of being associated with the development of secondary leukemia. Our purpose was to determine the effects of etoposide on different genomic regions, aiming at discovering whether there are preferential sites which can be targeted by this drug in peripheral lymphocytes from healthy individuals. The in vitro treatment with low doses of etoposide (0.25, 0.5, and 1 µg/mL, in 1 hour-pulse or continuous-48 h treatment) induced a significant increase in chromosomal aberrations, detected by conventional staining and FISH with specific probes for chromosomes 8 and 11, compared with untreated controls (p < 0.05). Additionally, the frequencies of alterations at 11q23, detected by MLL specific probes, were significantly higher (p < 0.005) in treated cells than in controls. In contrast, an analysis of rearrangements involving the IGH gene did not disclose differences between treatments. The present results demonstrated the potential of etoposide to interact with preferential chromosome sites in human lymphocytes, even at concentrations below the mean plasma levels measured in cancer patients. This greater susceptibility to etoposide-induced cleavage may explain the more frequent involvement of MLL in treatment-related leukemia.
Assuntos
Humanos , Adulto , Etoposídeo , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Aberrações Cromossômicas , Análise Citogenética , DNA Topoisomerases Tipo II , Hibridização in Situ Fluorescente , Neoplasias/tratamento farmacológico , Translocação GenéticaRESUMO
BACKGROUND: Cytogenetic abnormalities are one of the most reliable prognostic factors in acute leukemia. Combination of conventional chromosome analysis (CCA) and FISH provides higher sensitivity in detecting these genetic abnormalities, and it is effective to apply several FISH probes as a profile test. The objective of this study was to investigate the utility of FISH profile analyses in the initial diagnosis of acute leukemia. METHODS: Two hundred and forty one de novo acute leukemia patients diagnosed from January, 2002 to November, 2007 were included. For acute lymphoblastic leukemia profile test, FISH probes for BCR/ABL, TEL/AML1, MLL gene rearrangement and CDKN2A deletion were used. For acute myeloid leukemia profile test, probes for AML1/ETO, MLL and CBFbeta gene rearrangement were used. The results of CCA and FISH profile tests were collected, and the positive rates were compared. RESULTS: ALL FISH profile tests revealed additional genetic aberrations not detected by chromosome analysis in 48.6% (67/138) of cases, including those with normal karyotypes or no mitotic cells (37%, 51/138). Among these 51 cases, TEL/AML1 abnormalities were detected in 44.3%, followed by the abnormal CDKN2A signal (24.6%) and hyperdiploidy (18.0%). AML FISH profile tests revealed additional genetic abnormalities in 7.8% (8/103) of cases. CONCLUSIONS: FISH analysis as a profile test detected additional genetic aberrations in a significant proportion of acute leukemia, and was effective especially in detecting cryptic translocations, submicroscopic deletions and complex karyotypes. Our study supports the need to incorporate FISH profile test at initial work up in acute leukemia.
Assuntos
Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Aberrações Cromossômicas , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Hibridização in Situ Fluorescente/métodos , Cariotipagem , Leucemia Mieloide Aguda/diagnóstico , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Proteínas Proto-Oncogênicas c-bcr/genéticaRESUMO
Cellular quiescence is characterized not only by reduced mitotic and metabolic activity but also by altered gene expression. Growing evidence suggests that quiescence is not merely a basal state but is regulated by active mechanisms. To understand the molecular programme that governs reversible cell cycle exit, we focused on quiescence-related gene expression in a culture model of myogenic cell arrest and activation. Here we report the identification of quiescence-induced genes using a gene-trap strategy. Using a retroviral vector, we generated a library of gene traps in C2C12 myoblasts that were screened for arrest-induced insertions by live cell sorting (FACS-gal). Several independent gene- trap lines revealed arrest-dependent induction of betagal activity, confirming the efficacy of the FACS screen.The locus of integration was identified in 15 lines. In three lines,insertion occurred in genes previously implicated in the control of quiescence, i.e. EMSY - a BRCA2--interacting protein, p8/com1 - a p300HAT -- binding protein and MLL5 - a SET domain protein. Our results demonstrate that expression of chromatin modulatory genes is induced in G0, providing support to the notion that this reversibly arrested state is actively regulated.
Assuntos
Animais , Northern Blotting , Southern Blotting , Técnicas de Cultura de Células , Ciclo Celular , Diferenciação Celular/genética , Proliferação de Células , Células Cultivadas , Meios de Cultura , Proteínas de Ligação a DNA/genética , Citometria de Fluxo , Regulação da Expressão Gênica/genética , Biblioteca Gênica , Genes/fisiologia , Genes Virais , Vetores Genéticos , Camundongos , Proteínas dos Microfilamentos/genética , Modelos Biológicos , Mutagênese Insercional , Proteína de Leucina Linfoide-Mieloide/genética , Mioblastos/citologia , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Retroviridae/genética , Transdução Genética , beta-Galactosidase/análiseRESUMO
Acute leukemia in early childhood is biologically and clinically distinct. The particular characteristics of this malignancy diagnosed during the first months of life have provided remarkable insights into the etiology of the disease. The pro-B, CD10 negative immunophenotype is typically found in infant acute leukemia, and the most common genetic alterations are the rearrangements of the MLL gene. In addition, the TEL/AML1 fusion gene is most frequently found in children older than 24 months. A molecular study on a Brazilian cohort (age range 0-23 months) has detected TEL/AML1+ve (N = 9), E2A/PBX1+ve (N = 4), PML/RARA+ve (N = 4), and AML1/ETO+ve (N = 2) cases. Undoubtedly, the great majority of genetic events occurring in these patients arise prenatally. The environmental exposure to damaging agents that give rise to genetic changes prenatally may be accurately determined in infants since the window of exposure is limited and known. Several studies have shown maternal exposures that may give rise to leukemogenic changes. The Brazilian Collaborative Study Group of Infant Acute Leukemia has found that mothers exposed to dipyrone, pesticides and hormones had an increased chance to give birth to babies with infant acute leukemia [OR = 1.48 (95 percentCI = 1.05-2.07), OR = 2.27 (95 percentCI = 1.56-3.31) and OR = 9.08 (95 percentCI = 2.95-27.96)], respectively. This review aims to summarize recent clues that have facilitated the elucidation of the biology of early childhood leukemias, with emphasis on infant acute leukemia in the Brazilian population.
Assuntos
Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Regulação Neoplásica da Expressão Gênica , Leucemia Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/genética , Efeitos Tardios da Exposição Pré-Natal , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia Mieloide/epidemiologia , Leucemia Mieloide/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologiaRESUMO
Acute basophilic leukaemia is an uncommon form of acute leukaemia, rarely occurring as de novo disease. Due to rarity of the disease, consistent diagnostic criteria for the identification of this entity still remain the topic of discussion. Immunophenotypic profile, electron microscopy and cytogenetic analysis in addition to morphological features, are said to be highly desirable for correct identification of this entity. In set-up like ours, where such facilities are either not available or not in reach of the patients due to financial constraints, morphological features and simple technique like demonstration of metachromasia in blasts with toluidine blue stain remain the most useful diagnostic tool for identification of this rare condition. We present a case of acute basophilic leukaemia with (11q23)-MLL gene rearrangement, in an 18-year-old male with review of literature and discussion of diagnostic criteria.