RESUMEN
The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety-eight young adults (range: 21-60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54-myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of -5/5q- (P < .001) and -17/17p- (P < .001), but not -7/7q- (P = .370). This "typical" CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia-free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR-246 that targeted mutant p53, but resistant to MDM2 antagonist MI-77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.
Asunto(s)
Cariotipo Anormal , Antineoplásicos/administración & dosificación , Cromosomas Humanos , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda , Monosomía , Proteína p53 Supresora de Tumor , Adolescente , Adulto , Cromosomas Humanos/genética , Cromosomas Humanos/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
OBJECTIVES: To report the demonstration of double minutes with MYC amplification in a case of myeloproliferative neoplasm with monocytosis in transformation by a combination of standard karyotyping and interphase and metaphase fluorescence in situ hybridization (FISH). METHODS: To determine the lineage involvement, we applied combined morphology and an interphase FISH study using dual-color break-apart probes for MYC on peripheral blood film. RESULTS: MYC amplification was demonstrated in both myeloid and monocytic cells but not lymphocytes. The MYC amplification was not associated with loss of MYC signals at the homologous 8q24 regions where the genes were located. Furthermore, the extent of MYC amplification has been shown to diminish as the granulocytes mature. CONCLUSIONS: Combined morphology and FISH study has shown a pluripotent myeloid disorder and also an inverse relationship between cell maturity and MYC amplification.
Asunto(s)
Cromatina/genética , Leucemia Mielomonocítica Crónica/genética , Proteínas Proto-Oncogénicas c-myc/genética , Anciano de 80 o más Años , Cromatina/patología , Colorantes , Eosina Amarillenta-(YS) , Femenino , Amplificación de Genes , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielomonocítica Crónica/patología , Azul de MetilenoRESUMEN
Dicentric assay is the international gold standard for cytogenetic biodosimetry after radiation exposure, despite being very labour-intensive, time-consuming, and highly expertise-dependent. It involves the identification of centromeres and structure of solid-stained chromosomes and the enumeration of dicentric chromosomes in a large number of first-division metaphases of cultured T lymphocytes. The dicentric yield is used to estimate the radiation exposure dosage according to a statistically derived and predetermined dose-response curve. It can be used for population triage after large-scale accidental over-exposure to ionising radiation or with a view to making clinical decisions for individual patients receiving substantial radiation. In this report, we describe our experience in the establishment of a cytogenetic biodosimetry laboratory in Queen Elizabeth Hospital, Hong Kong. This was part of the contingency plan for emergency measures against radiation accidents at nuclear power stations.
Asunto(s)
Relación Dosis-Respuesta en la Radiación , Dosis de Radiación , Monitoreo de Radiación/métodos , Liberación de Radiactividad Peligrosa/prevención & control , Bioensayo , Cromosomas Humanos/efectos de la radiación , Análisis Citogenético , Femenino , Hong Kong , Humanos , Masculino , Plantas de Energía Nuclear , Radiación Ionizante , Radiometría , Medición de RiesgoAsunto(s)
Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda/genética , Translocación Genética , Anciano , Biomarcadores de Tumor/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Proteínas Proto-Oncogénicas/genética , Proteína 1 Compañera de Translocación de RUNX1 , Cariotipificación Espectral , Factores de Transcripción/genéticaAsunto(s)
Médula Ósea/patología , Crioglobulinemia/patología , Linfoma de Células B de la Zona Marginal/patología , Anciano , Anemia Ferropénica/complicaciones , Células de la Médula Ósea/patología , Cromatina/metabolismo , Crioglobulinemia/complicaciones , Resultado Fatal , Humanos , Cariotipificación , Ganglios Linfáticos/patología , Linfoma de Células B de la Zona Marginal/complicaciones , MasculinoRESUMEN
JAK2 V617F mutation is mostly seen in BCR-ABLI negative myeloproliferative neoplasms. Among other myeloid neoplasms, it occurs with remarkably high frequency in refractory anemia with ring sideroblasts associated with marked thrombocytosis, a group of myeloid neoplasms with both dysplastic and proliferative features. It has also been reported in occasional cases of myelodysplastic syndrome with isolated del(5q), often with a diagnosis of refractory cytopenia with multilineage dysplasia. We performed a retrospective analysis of JAK2 V617F mutation in Chinese patients with myeloid neoplasms and isolated del(5q), and were able to demonstrate the frequent occurrence of JAK2 V617F mutation in 5q- syndrome.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Janus Quinasa 2/genética , Síndromes Mielodisplásicos/genética , Mutación Puntual , Adulto , Anciano , Anciano de 80 o más Años , Anemia Refractaria con Exceso de Blastos/enzimología , Anemia Refractaria con Exceso de Blastos/genética , Codón/genética , Progresión de la Enfermedad , Femenino , Hong Kong/epidemiología , Humanos , Cariotipificación , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Persona de Mediana Edad , Síndromes Mielodisplásicos/enzimología , Estudios Retrospectivos , SíndromeAsunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 3/ultraestructura , Janus Quinasa 2/genética , Leucemia Mieloide/genética , Mutación Missense , Síndromes Mielodisplásicos/genética , Mutación Puntual , Translocación Genética , Enfermedad Aguda , Adulto , Anciano , Anemia Refractaria con Exceso de Blastos/genética , Cromosomas Humanos Par 3/genética , Cromosomas Humanos Par 7 , Progresión de la Enfermedad , Femenino , Hong Kong/epidemiología , Humanos , Leucemia Mieloide/epidemiología , Masculino , Persona de Mediana Edad , Monosomía , Síndromes Mielodisplásicos/epidemiología , Síndrome , Trombocitosis/etiologíaAsunto(s)
Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda/genética , Translocación Genética , Adulto , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/patología , Proteínas de Fusión Oncogénica/genética , Proteína 1 Compañera de Translocación de RUNX1 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sarcoma Mieloide/complicacionesRESUMEN
A Chinese girl presented with generalized papular rash and monocytic leukemia 19 days after birth. Cytogenetic analysis showed t(8;16)(p11.2;p13.3) as the sole chromosomal abnormality. Spontaneous regression of the leukemia was observed after 2 months, although the t(8;16) translocation persisted cytogenetically. This was followed 7 months later by the development of acute myeloid leukemia with maturation and cytogenetic evolution with extra chromosomes 4 and 8. Molecular study showed that the reciprocal MYST3 and CREBBP gene fusion characteristic of t(8;16) translocation persisted throughout the clinical course, even during spontaneous regression of the neonatal leukemia, and after chemotherapy-induced remission of the subsequent acute myeloid leukemia. The genetic lesion only became undetectable at the molecular level at the age of 20 months. The possible role of MYST3 and CREBBP gene fusion in the pathogenesis of the leukemia is discussed.
Asunto(s)
Leucemia Monocítica Aguda/genética , Leucemia Mieloide Aguda/genética , Translocación Genética , Proteína de Unión a CREB/genética , Cromosomas Humanos Par 8 , Femenino , Fusión Génica , Histona Acetiltransferasas/genética , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/tratamiento farmacológico , Remisión EspontáneaAsunto(s)
Síndrome Hipereosinofílico/genética , Hibridación Fluorescente in Situ , Proteínas de Fusión Oncogénica/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Factores de Escisión y Poliadenilación de ARNm/genética , Adulto , Antineoplásicos/uso terapéutico , Benzamidas , Enfermedad Crónica , Eliminación de Gen , Reordenamiento Génico , Humanos , Síndrome Hipereosinofílico/tratamiento farmacológico , Mesilato de Imatinib , Masculino , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Natural killer (NK) cell lymphomas lack suitable clonal markers for tumour cell detection, making the monitoring of minimal residual lymphoma difficult. Aberrant promoter CpG methylation occurs frequently in NK cell lymphomas. The objective of this study was to assess the potential of aberrant methylation as a surrogate tumour marker. Twenty-five primary tumours and 105 serial biopsies taken at various time points after treatment were examined using a methylation-specific polymerase chain reaction (MSP) for a panel of genes, comprising p73, p16, hMLH1, RARbeta and p15, previously shown to be methylated in NK cell lymphomas. All samples underwent independent morphological examination, supplemented by immunostaining for CD56 and in-situ hybridization for Epstein-Barr-virus-encoded RNA. Primary tumours showed the frequent methylation of the genes p73 (92%), p16 (71%), hMLH1 (61%), RARbeta (56%) and p15 (48%). MSP results in serial post-treatment biopsies were correlated with clinicopathological findings. Results were concordant in 89 follow-up samples (18 samples, histology positive/MSP positive; 71 samples, histology negative/MSP negative) and discordant in 16. Fifteen samples were histology negative/MSP positive, and tumour involvement was subsequently confirmed (positive re-biopsies or relapses at the same sites), indicating that MSP was more sensitive for minimal lymphoma detection. One sample was histology positive/MSP negative; a subsequent histological review and continuous clinical remission of the patient did not support tumour involvement. Our findings suggest that MSP for aberrantly methylated genes is a potentially valuable molecular marker for detecting either residual or relapsed disease in NK cell lymphoma patients.