ABSTRACT
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.
Subject(s)
Abnormal Karyotype , Antineoplastic Agents/administration & dosage , Chromosomes, Human , Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute , Monosomy , Tumor Suppressor Protein p53 , Adolescent , Adult , Chromosomes, Human/genetics , Chromosomes, Human/metabolism , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Female , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
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.
Subject(s)
Dose-Response Relationship, Radiation , Radiation Dosage , Radiation Monitoring/methods , Radioactive Hazard Release/prevention & control , Biological Assay , Chromosomes, Human/radiation effects , Cytogenetic Analysis , Female , Hong Kong , Humans , Male , Nuclear Power Plants , Radiation, Ionizing , Radiometry , Risk AssessmentSubject(s)
Chromosomes, Human, Pair 21 , Chromosomes, Human, Pair 8 , Leukemia, Myeloid, Acute/genetics , Translocation, Genetic , Adult , Core Binding Factor Alpha 2 Subunit/genetics , Female , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/pathology , Oncogene Proteins, Fusion/genetics , RUNX1 Translocation Partner 1 Protein , Reverse Transcriptase Polymerase Chain Reaction , Sarcoma, Myeloid/complicationsABSTRACT
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.
Subject(s)
Chromatin/genetics , Leukemia, Myelomonocytic, Chronic/genetics , Proto-Oncogene Proteins c-myc/genetics , Aged, 80 and over , Chromatin/pathology , Coloring Agents , Eosine Yellowish-(YS) , Female , Gene Amplification , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myelomonocytic, Chronic/pathology , Methylene BlueABSTRACT
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.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5/genetics , Janus Kinase 2/genetics , Myelodysplastic Syndromes/genetics , Point Mutation , Adult , Aged , Aged, 80 and over , Anemia, Refractory, with Excess of Blasts/enzymology , Anemia, Refractory, with Excess of Blasts/genetics , Codon/genetics , Disease Progression , Female , Hong Kong/epidemiology , Humans , Karyotyping , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Middle Aged , Myelodysplastic Syndromes/enzymology , Retrospective Studies , SyndromeABSTRACT
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.
Subject(s)
Leukemia, Monocytic, Acute/genetics , Leukemia, Myeloid, Acute/genetics , Translocation, Genetic , CREB-Binding Protein/genetics , Chromosomes, Human, Pair 8 , Female , Gene Fusion , Histone Acetyltransferases/genetics , Humans , Infant , Infant, Newborn , Leukemia, Myeloid, Acute/drug therapy , Remission, SpontaneousSubject(s)
Chromosomes, Human, Pair 21 , Chromosomes, Human, Pair 8 , Leukemia, Myeloid, Acute/genetics , Translocation, Genetic , Aged , Biomarkers, Tumor/metabolism , Core Binding Factor Alpha 2 Subunit/genetics , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Male , Proto-Oncogene Proteins/genetics , RUNX1 Translocation Partner 1 Protein , Spectral Karyotyping , Transcription Factors/geneticsSubject(s)
Bone Marrow/pathology , Cryoglobulinemia/pathology , Lymphoma, B-Cell, Marginal Zone/pathology , Aged , Anemia, Iron-Deficiency/complications , Bone Marrow Cells/pathology , Chromatin/metabolism , Cryoglobulinemia/complications , Fatal Outcome , Humans , Karyotyping , Lymph Nodes/pathology , Lymphoma, B-Cell, Marginal Zone/complications , MaleSubject(s)
Chromosome Inversion , Chromosomes, Human, Pair 3/ultrastructure , Janus Kinase 2/genetics , Leukemia, Myeloid/genetics , Mutation, Missense , Myelodysplastic Syndromes/genetics , Point Mutation , Translocation, Genetic , Acute Disease , Adult , Aged , Anemia, Refractory, with Excess of Blasts/genetics , Chromosomes, Human, Pair 3/genetics , Chromosomes, Human, Pair 7 , Disease Progression , Female , Hong Kong/epidemiology , Humans , Leukemia, Myeloid/epidemiology , Male , Middle Aged , Monosomy , Myelodysplastic Syndromes/epidemiology , Syndrome , Thrombocytosis/etiologyABSTRACT
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.