RESUMO
A new dic(7;12)(p12.21;p12.2) chromosome aberration was identified in an acute myeloid leukemia with FAB-M1 morphology and was cloned. Fluorescence in situ hybridization and genomic quantitative polymerase chain reaction mapping experiments revealed the precise localization of the breakpoints, at 7p12, just 5' to the GRB10 gene, and 12p11, within a genomic region containing no known genes. As a result, a new dicentric chromosome is created, dic(7;12), with the consequent deletion of 50 Mb at 7p, from the telomere to the GRB10 region, and of 30 Mb at 12p, from the telomere to p11. Several genes are included in the affected areas.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 7 , Leucemia Mieloide Aguda/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Transgenic expression of the abnormal products of acute myeloid leukemia-associated (AML-associated) primary chromosomal translocations in hematopoietic stem/progenitor cells initiates leukemogenesis in mice, yet additional mutations are needed for leukemia development. We report here aberrant expression of PR domain containing 16 (PRDM16) in AML cells with either translocations of 1p36 or normal karyotype. These carried, respectively, relatively high prevalence of mutations in the TP53 tumor suppressor gene and in the nucleophosmin (NPM) gene, which regulates p53. Two protein isoforms are expressed from PRDM16, which differ in the presence or absence of the PR domain. Overexpression of the short isoform, sPRDM16, in mouse bone marrow induced AML with full penetrance, but only in the absence of p53. The mouse leukemias were characterized by multilineage cellular abnormalities and megakaryocyte dysplasia, a common feature of human AMLs with 1p36 translocations or NPM mutations. Overexpression of sPRDM16 increased the pool of HSCs in vivo, and in vitro blocked myeloid differentiation and prolonged progenitor life span. Loss of p53 augmented the effects of sPRDM16 on stem cell number and induced immortalization of progenitors. Thus, overexpression of sPRDM16 induces abnormal growth of stem cells and progenitors and cooperates with disruption of the p53 pathway in the induction of myeloid leukemia.
Assuntos
Transformação Celular Neoplásica/metabolismo , Proteínas de Ligação a DNA/biossíntese , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição/biossíntese , Proteína Supressora de Tumor p53 , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Diferenciação Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Senescência Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Estrutura Terciária de Proteína/genética , Fatores de Transcrição/genética , Translocação Genética , Proteína Supressora de Tumor p53/genéticaRESUMO
Rearrangement of the BCL6 gene is found in follicular lymphomas and in diffuse large B cell lymphomas of follicular center cell origin. The breakpoints cluster mainly in a region spanning the first noncoding exon of the gene (the major breakpoint region). A second breakpoint cluster has also been identified upstream of the first BCL6 noncoding exon (the alternative breakpoint region [ABR]). To date, eight different rearrangements involving the ABR have been reported. Here, we describe a novel rearrangement involving a t(2;3)(p11;q27) translocation that affects the ABR in an unusual combination with the IGK locus.
Assuntos
Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Linfoma Folicular/genética , Translocação Genética/genética , Idoso , Rearranjo Gênico , Humanos , Imunoglobulinas/genética , Linfoma Folicular/classificação , Masculino , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcl-6/genéticaRESUMO
8p11 myeloproliferative syndrome (EMS) is a clinical-pathologic entity characterized by rearrangements involving the FGFR1 gene, which encodes a receptor tyrosine kinase. These rearrangements invariably lead to aberrant fusion proteins in which the kinase activity is constitutively turned on, with resulting oncogenic properties. In this article, we describe a new translocation in EMS, t(7;8)(q34;p11), in which the FGFR1 gene is fused to a previously unidentified partner, the TIF1 gene. We show that both the TIF1-FGFR1 and FGFR1-TIF1 fusion proteins have the potential to be translated as a result of the translocation. Thus, our data extend the involvement of FGFR1 in EMS and lend support to the concept that there is a precise correlation between genotype and phenotype in this disease.
