Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Point Mutation , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins c-abl/genetics , Adult , Drug Resistance, Neoplasm , Fusion Proteins, bcr-abl/genetics , Humans , Male , Protein Kinase Inhibitors/pharmacologySubject(s)
Janus Kinase 2/genetics , Pruritus/pathology , Water/adverse effects , Diagnostic Screening Programs , Erythropoietin/blood , Female , Humans , Male , Middle Aged , Mutation , Myeloproliferative Disorders/complications , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/pathology , Polycythemia Vera/complications , Polycythemia Vera/diagnosis , Polycythemia Vera/genetics , Polycythemia Vera/pathology , Pruritus/etiology , Retrospective StudiesSubject(s)
Janus Kinase 2/genetics , Mutation , Myeloproliferative Disorders/genetics , Consensus , HumansABSTRACT
PURPOSE: Chronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification. MATERIALS AND METHODS: A next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients. RESULTS: Next-generation sequencing confirmed the CSF3R T618I in all patients with identification of concurrent SRSF2, SETBP1, NRAS and CBL mutations at diagnosis. At blast crisis, clonal evolution was evidenced by an increased CSF3R T618I allele frequency and by loss or acquisition of CBL and NRAS mutations. CONCLUSION: The diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.
Subject(s)
Blast Crisis/genetics , High-Throughput Nucleotide Sequencing/methods , Leukemia, Neutrophilic, Chronic/genetics , Leukemia, Neutrophilic, Chronic/pathology , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , MutationSubject(s)
Consensus , Molecular Diagnostic Techniques/methods , Myeloproliferative Disorders/genetics , DNA Mutational Analysis , Genetic Markers/genetics , Humans , Ireland , Janus Kinase 2/genetics , Molecular Diagnostic Techniques/standards , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/enzymology , Practice Guidelines as TopicSubject(s)
Biomarkers, Tumor/genetics , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/therapy , Mutation, Missense , Receptors, Colony-Stimulating Factor/genetics , Allografts , Base Sequence , DNA, Neoplasm/genetics , Female , Humans , Male , Middle Aged , Stem Cell Transplantation , Time FactorsABSTRACT
We report on a patient who developed donor-derived cutaneous T-cell lymphoma (CTCL) 4 years after successful treatment of chronic myeloid leukaemia with an allogeneic bone marrow transplant. The patient developed an eczematous rash unresponsive to topical therapy and immunosuppression. When CTCL was diagnosed in the recipient, his sibling donor had been attending his local dermatology unit with a maculosquamous rash, which proved subsequently to be mycosis fungoides. An identical pattern of donor and recipient clonality assessment and T-cell receptor gene sequencing indicated that the CTCL was probably transmitted in the bone marrow harvest. This suggests that CTCL cells circulate in the marrow at an early subclinical stage in this disease. This is the second case of donor-derived CTCL reported to date.
Subject(s)
Bone Marrow Transplantation/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Mycosis Fungoides/etiology , Skin Neoplasms/etiology , Humans , Male , Middle Aged , Siblings , Transplantation, Homologous/adverse effectsABSTRACT
Hairy cell leukaemia (HCL) has distinct clinical, morphological and immunophenotypic features with no recurrent cytogenetic or molecular abnormalities reported until the recent description of the BRAF V600E mutation in patients with classical HCL. The incidence of this mutation was sought in 27 patients with either classical HCL or HCL variant by an allele-specific PCR approach and findings related to morphology, cytochemistry and immunophenotype. A high degree of correlation was noted between the presence of BRAF V600E and established diagnostic criteria in 26/27 patients with HCL/HCL variant. Detection of the BRAF V600E mutation is therefore a useful adjunct in the differential diagnosis of HCL and HCL variant and highlights the value of a multifaceted approach to the diagnosis of this malignancy.
Subject(s)
Leukemia, Hairy Cell/diagnosis , Leukemia, Hairy Cell/genetics , Mutation , Proto-Oncogene Proteins B-raf/genetics , Adult , Aged , Aged, 80 and over , Bone Marrow Cells/pathology , Diagnosis, Differential , Female , Genetic Variation , Histocytochemistry , Humans , Immunophenotyping , Male , Middle Aged , Retrospective StudiesSubject(s)
Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Amino Acid Sequence , Base Sequence , Female , Humans , Introns , Middle Aged , Molecular Sequence Data , Real-Time Polymerase Chain Reaction , Sequence DeletionSubject(s)
Gene Expression Regulation, Leukemic , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Receptors, Cytokine/genetics , Adolescent , Adult , Aged , Female , Genetic Testing , Humans , In Situ Hybridization, Fluorescence , Karyotype , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Reverse Transcriptase Polymerase Chain Reaction , Young AdultABSTRACT
BACKGROUND: Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells. Approximately half of all adult AML patients have a normal karyotype (NK-AML) and an intermediate risk prognosis. AIMS: To determine the incidence and prognostic significance of NPM1 and FLT3-ITD mutations in a population of patients with NK-AML. METHODS: FLT3-ITD and NPM1 mutation status was retrospectively sought in presentation samples from 44 NK-AML patients. RESULTS: FLT3-ITD and NPM1 mutations were detected in 45.5 and 54.5% of patients, respectively, allowing stratification according to genotype. CONCLUSIONS: FLT3-ITD and NPM1 mutation status can be defined in NK-AML. Prospective screening for these mutations is advocated in all NK-AML patients, as the genotype is of clinical importance when considering treatment options including stem cell transplantation.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Nuclear Proteins/genetics , Phosphoproteins/genetics , fms-Like Tyrosine Kinase 3/genetics , Adolescent , Adult , Aged , Electrophoresis, Agar Gel , Female , Genotype , Humans , Male , Middle Aged , Mutation , Nucleophosmin , Prognosis , Retrospective Studies , Seroepidemiologic Studies , XYY Karyotype , Young AdultSubject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Neoplasm Recurrence, Local/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Transplantation Chimera , Benzamides , Drug Resistance, Neoplasm/genetics , Hematopoietic Stem Cell Transplantation , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Lymphocyte Transfusion , Male , Middle Aged , Transplantation, HomologousABSTRACT
BACKGROUND: The chronic myeloproliferative disorders (MPD) are clonal haemopoietic stem cell disorders. AIMS: The incidence of JAK2 V617F mutation was sought in a population of patients with MPD. METHODS: The JAK2 V617 mutation status was determined in 79 patients with known MPD and 59 patients with features suggestive of MPD. RESULTS: The mutation was found in patients with polycythaemia vera, essential thrombocythaemia, idiopathic myelofibrosis and in patients with other chronic myeloproliferative disorders. Eight JAK2 V617F positive cases were identified amongst those patients with features suggestive of MPD. CONCLUSIONS: The incidence of the JAK2 V617F mutation in MPD patients is similar to that reported by other groups. The assay confirmed and refined the diagnosis of several patients with features indicative of MPD. We suggest screening for this mutation in all patients with known and suspected MPD as identification is valuable in classification and is a potential target for signal transduction therapy.
Subject(s)
Janus Kinase 2/genetics , Myeloproliferative Disorders/genetics , Chronic Disease , Humans , Mutation , Polycythemia Vera/genetics , Polymerase Chain Reaction , Primary Myelofibrosis/genetics , Thrombocythemia, Essential/geneticsABSTRACT
Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder caused by mutations in one of seven known genes (FANCA,C,D2,E,F,G and BRCA2). Mutations in the FANCA gene are the most prevalent, accounting for two-thirds of FA cases. Affected individuals have greatly increased risks of acute myeloid leukemia (AML). This raises the question as to whether inherited or acquired mutations in FA genes might be involved in the development of sporadic AML. Quantitative fluorescent PCR was used to screen archival DNA from sporadic AML cases for FANCA deletions, which account for 40% of FANCA mutations in FA homozygotes. Four heterozygous deletions were found in 101 samples screened, which is 35-fold higher than the expected population frequency for germline FANCA deletions (P<0.0001). Sequencing FANCA in the AML samples with FANCA deletions did not detect mutations in the second allele and there was no evidence of epigenetic silencing by hypermethylation. However, real-time quantitative PCR analysis in these samples showed reduced expression of FANCA compared to nondeleted AML samples and to controls. These findings suggest that gene deletions and reduced expression of FANCA may be involved in the promotion of genetic instability in a subset of cases of sporadic AML.