RESUMEN
Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the NPM1 gene, followed by DNMT3A, FLT3 and NRAS. An unexpected co-occurrence of KMT2A translocation and DNMT3A-R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.
Asunto(s)
Leucemia Mieloide Aguda/genética , Tasa de Mutación , Variaciones en el Número de Copia de ADN , ADN Metiltransferasa 3A/genética , GTP Fosfohidrolasas/genética , Pruebas Genéticas/estadística & datos numéricos , Secuenciación de Nucleótidos de Alto Rendimiento , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Leucemia Mieloide Aguda/patología , Proteínas de la Membrana/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Nucleofosmina/genética , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
We present the case of a 71-year-old woman diagnosed with chronic lymphocytic leukemia who received multiple chemotherapeutic lines and evolved to acute lymphoblastic leukemia. The patient was Rai stage 0 at the time of the diagnosis and was monitored for almost 9 years. After that, the disease progressed and the patient began chemotherapy (fludarabine/cyclophosphamide combination), obtained complete remission and relapsed one year later after finishing treatment. She received multiple therapeutic regimens, accompanied by multiple infectious complications. After 8 years of evolution since she started chemotherapy, bone marrow aspirate and immunophenotyping revealed acute lymphoblastic leukemia. The occurrence of acute leukemia in CLL is rare and may arise from the same clone; however, most cases appear after patients have received chemotherapy, suggesting that they are therapy-related.
Asunto(s)
Antineoplásicos Alquilantes/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Neoplasias Primarias Secundarias , Leucemia-Linfoma Linfoblástico de Células Precursoras/inducido químicamente , Anciano , Resultado Fatal , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/complicacionesRESUMEN
Differential UV spectroscopy was used to study the temperature dependence of the conformational equilibrium in aqueous poly I . poly A . poly I (A2I) solutions containing Na+ (0.1-2 M) and Mg2+ (10(-5)-0.005 M) ions. Over the whole range of the studied Na+ and Mg2+ concentrations, the heating-induced destruction of the triple A2I helix is actually the A2I --> A + I + I (3 --> 1) transition. The rise of the transition temperature with increasing Na+ and Mg2+ contents is well described by Manning's and the "ligand" theories, which makes it possible to estimate the linear charge density on the single-stranded poly I (xi = 1.9 +/- 0.1) and the Mg2+-A2I binding constant (K = 1,250 M(-1) for the zero degree of binding). An analytical expression has been obtained, which correlates the constants of Mg2+ binding to three- and single-stranded polynucleotides (K3 and K1, respectively) and the linear charge density on them. There are only minor distinctions between the K3 values for A2U and A2I because these polynucleotides have similar structures. The difference in the K1 values is also slight as single-stranded poly U, poly I, and poly A have similar conformations. Dependence of the conformational transition temperatures of two triple helices with changing Mg2+ concentration.