RESUMO
Autoimmune diseases develop in approximately 5% of humans. They can arise when self-tolerance checkpoints of the immune system are bypassed as a consequence of inherited mutations of key genes involved in lymphocyte activation, survival, or death. For example, autoimmune lymphoproliferative syndrome (ALPS) results from defects in self-tolerance checkpoints as a consequence of mutations in the death receptor-encoding gene TNF receptor superfamily, member 6 (TNFRSF6; also known as FAS). However, some mutation carriers remain asymptomatic throughout life. We have now demonstrated in 7 ALPS patients that the disease develops as a consequence of an inherited TNFRSF6 heterozygous mutation combined with a somatic genetic event in the second TNFRSF6 allele. Analysis of the patients' CD4(-)CD8(-) (double negative) T cells--accumulation of which is a hallmark of ALPS--revealed that in these cells, 3 patients had somatic mutations in their second TNFRSF6 allele, while 4 patients had loss of heterozygosity by telomeric uniparental disomy of chromosome 10. This observation provides the molecular bases of a nonmalignant autoimmune disease development in humans and may shed light on the mechanism underlying the occurrence of other autoimmune diseases.
Assuntos
Síndrome Linfoproliferativa Autoimune/genética , Mutação , Receptor fas/genética , Adolescente , Adulto , Síndrome Linfoproliferativa Autoimune/imunologia , Cromossomos Humanos Par 10/genética , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Perda de Heterozigosidade , Linfócitos Nulos/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Linhagem , Dissomia Uniparental , Adulto JovemRESUMO
Posttranscriptional modifications of histones play important roles in the control of chromatin structure and transcription. H3K4 (histone H3 lysine 4) methylation by the SET domain of the trithorax-group protein MLL (mixed-lineage leukemia) is important for the control of homeobox (HOX) gene expression during development. MLL is tethered to the HOXA locus through interaction of its amino-terminus with menin. MLL fusion proteins associated with human leukemia contain the menin interaction peptide and frequently recruit H3K79 (histone H3 lysine 79) methylation activity. This allows sustained expression of HOXA genes important for cellular transformation. We have characterized a novel recurrent chromosomal aberration, inv(11)(p15q23), as an isolated chromosomal abnormality in 2 patients with acute myeloid leukemia. This aberration is predicted to result in the expression of an NUP98 (nucleoporin 98 kDa)-MLL fusion protein that is unable to interact with menin. As expected, low levels of HOXA gene expression were observed in the patients' samples. This fusion protein is predicted to participate in cellular transformation by activating MLL targets other than HOXA genes.
Assuntos
Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Adulto , Idoso , Sequência de Bases , Transformação Celular Neoplásica/genética , Inversão Cromossômica , Cromossomos Humanos Par 11/genética , Primers do DNA/genética , DNA de Neoplasias/genética , Feminino , Expressão Gênica , Genes Homeobox , Histona-Lisina N-Metiltransferase , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Proteína de Leucina Linfoide-Mieloide/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Fusão Oncogênica , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas/metabolismoRESUMO
BACKGROUND: The myelodysplastic syndromes and myeloproliferative disorders are associated with deregulated production of myeloid cells. The mechanisms underlying these disorders are not well defined. METHODS: We conducted a combination of molecular, cytogenetic, comparative-genomic-hybridization, and single-nucleotide-polymorphism analyses to identify a candidate tumor-suppressor gene common to patients with myelodysplastic syndromes, myeloproliferative disorders, and acute myeloid leukemia (AML). The coding sequence of this gene, TET2, was determined in 320 patients. We analyzed the consequences of deletions or mutations in TET2 with the use of in vitro clonal assays and transplantation of human tumor cells into mice. RESULTS: We initially identified deletions or mutations in TET2 in three patients with myelodysplastic syndromes, in three of five patients with myeloproliferative disorders, in two patients with primary AML, and in one patient with secondary AML. We selected the six patients with myelodysplastic syndromes or AML because they carried acquired rearrangements on chromosome 4q24; we selected the five patients with myeloproliferative disorders because they carried a dominant clone in hematopoietic progenitor cells that was positive for the V617F mutation in the Janus kinase 2 (JAK2) gene. TET2 defects were observed in 15 of 81 patients with myelodysplastic syndromes (19%), in 24 of 198 patients with myeloproliferative disorders (12%) (with or without the JAK2 V617F mutation), in 5 of 21 patients with secondary AML (24%), and in 2 of 9 patients with chronic myelomonocytic leukemia (22%). TET2 defects were present in hematopoietic stem cells and preceded the JAK2 V617F mutation in the five samples from patients with myeloproliferative disorders that we analyzed. CONCLUSIONS: Somatic mutations in TET2 occur in about 15% of patients with various myeloid cancers.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genética , Proteínas Proto-Oncogênicas/genética , Sequência de Aminoácidos , Animais , Antígenos CD34 , Cromossomos Humanos Par 4/genética , Hibridização Genômica Comparativa , Dioxigenases , Rearranjo Gênico , Células-Tronco Hematopoéticas/imunologia , Humanos , Janus Quinase 2/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Deleção de SequênciaRESUMO
The t(5;14)(q35;q32) chromosomal translocation is specifically observed in up to 20% of childhood T-cell acute lymphoblastic leukemia (T-ALL). It affects the BCL11B/CTIP2 locus on chromosome 14 and the RANBP17-TLX3/HOX11L2 region on chromosome 5. It leads to ectopic activation of TLX3/HOX11L2. To investigate the reasons of the association between t(5;14) and T-ALL, we isolated the translocation breakpoints in 8 t(5;14) patients. Sequence analyses did not involve recombinase activity in the genesis of the translocation. We used DNAse1 hypersensitive experiments to locate transcriptional regulatory elements downstream of BCL11B. By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3 promoter. Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3 to long-range cis-activating regions active during T-cell differentiation.
Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 5/genética , Proteínas de Ligação a DNA/genética , Proteínas de Homeodomínio/genética , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Oncogênicas/genética , Proteínas Repressoras/genética , Translocação Genética , Proteínas Supressoras de Tumor/genética , Diferenciação Celular/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Homeodomínio/biossíntese , Humanos , Células Jurkat , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/patologia , Proteínas Oncogênicas/biossíntese , Proteínas de Fusão Oncogênica/biossíntese , Regiões Promotoras Genéticas/genética , Proteínas Repressoras/biossíntese , Linfócitos T/metabolismo , Linfócitos T/patologia , Transcrição Gênica , Proteínas Supressoras de Tumor/biossínteseRESUMO
Since the RUNX1 gene contributes to megakaryopoiesis and acquired trisomy 21 is the most frequent numerical chromosome anomaly in acute megakaryoblastic leukemia (AMLK), a systematic study of RUNX1 abnormalities was performed by fluorescence in situ hybridization in AMLK patients. Four abnormalities were detected among 15 patients. One copy of RUNX1 was completeley or partially lost in three patients and translocated onto Xq24 in the fourth. The possible consequences of RUNX1 haploinsufficiency are discussed.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Deleção de Genes , Leucemia Megacarioblástica Aguda/genética , Adulto , Idoso , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-IdadeRESUMO
Two patients with Ph-positive chronic myelocytic leukemia in erythroblastic transformation and rearrangement of the short arm of chromosome 18 are reported. Fluorescence in situ hybridization studies showed that the 18p rearrangement resulted from translocation of the main part of chromosome 22 long arm to 18p, including BCR-ABL1 fusion. The 18p abnormality resulted, thus, in loss of 18p and duplication of BCR-ABL1 in both patients. The possible relation to the erythroblastic type of blastic phase is briefly discussed. In addition an apparently intact germline ABL1 gene was duplicated and inserted into chromosome 6 at band p21 in one of these patients.