RESUMO
The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival.
Assuntos
Calreticulina/genética , Janus Quinase 2/genética , Leucemia Mieloide Aguda/genética , Mutação , Mielofibrose Primária/genética , Trombocitemia Essencial/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fenótipo , Contagem de Plaquetas , Mielofibrose Primária/etiologia , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Receptores de Trombopoetina/genética , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Trombocitemia Essencial/complicações , Trombocitemia Essencial/mortalidade , Trombocitemia Essencial/patologiaAssuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Síndrome Hipereosinofílica/genética , Janus Quinase 2/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Pirazóis/farmacologia , Translocação Genética/efeitos dos fármacos , Idoso , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 9/genética , Análise Citogenética , Humanos , Síndrome Hipereosinofílica/tratamento farmacológico , Masculino , Nitrilas , Pirazóis/uso terapêutico , Pirimidinas , Indução de RemissãoRESUMO
BACKGROUND: In vitro experimental studies demonstrated that iron promotes free radical-induced low-density lipoprotein (LDL) oxidation. OBJECTIVE: To test the hypothesis that circulating oxidized LDL (oxLDL) levels might be associated with body iron stores (serum ferritin) and iron-related genetic markers (hemochromatosis gene C282Y mutation, haptoglobin polymorphism). METHODS: We investigated 381 (176 males, 205 females, age 45 +/- 6 years) healthy Caucasians. Serum oxLDL, assayed by a mAb-4E6-based enzyme-linked immunosorbent assay (ELISA), was expressed as oxLDL/LDL ratio to adjust for serum LDL-cholesterol concentration. Hemochromatosis gene C282Y mutation analysis was performed by a Taqman-based polymerase chain reaction (PCR) assay. Haptoglobin (Hp) phenotypes (Hp 1-1, Hp 2-1, Hp 2-2) were determined by starch gel electrophoresis. RESULTS: In stepwise multivariate regression analysis, gender (P < 0.0001), current smoking (P < 0.0001), HDL-cholesterol (P = 0.0001), ferritin (P = 0.0051), body mass index (BMI) (P = 0.0063), and Hp phenotype (P = 0.0331) independently predicted oxLDL/LDL ratio in the total group. In men, smoking (P < 0.0001), ferritin (P = 0.0052), Hp phenotype (P = 0.0063), and HDL-cholesterol (P = 0.0127) were independent determinants of oxLDL/LDL ratio. In women, only body mass index (P < 0.0001), HDL-cholesterol (P = 0.0005), and smoking (P = 0.0025) were significantly associated with oxLDL/LDL ratio. The C282Y mutation (wild-type versus C282Y heterozygotes) was not associated with oxLDL/LDL ratio in both sexes. CONCLUSION: Serum ferritin concentration and Hp polymorphism are independently associated with circulating oxLDL levels in males.
Assuntos
Ferritinas/sangue , Haptoglobinas/genética , Haptoglobinas/metabolismo , Ferro/metabolismo , Lipoproteínas LDL/sangue , Adulto , Feminino , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Polimorfismo Genético , Análise de RegressãoRESUMO
X-linked sideroblastic anemia and ataxia (XLSA-A) is a rare cause of early onset ataxia, which may be overlooked due to the usually mild asymptomatic anemia. The genetic defect has been identified as a mutation in the ABCB7 gene at Xq12-q13. The gene encodes a mitochondrial ATP-binding cassette (ABC) transporter protein involved in iron homeostasis. Until now only three families have been reported, each with a distinct missense mutation in this gene. We describe a fourth family with XLSA-A and a novel mutation in the ABCB7 gene.