RESUMO
OBJECTIVES: Kabuki syndrome (KS) is a rare congenital malformation syndrome associated with germline KMT2D mutations. Recurrent somatic mutations in KMT2D have frequently been observed in B-cell lymphoma, but limited studies are available that evaluate the genetic landscape of B-cell lymphomas in the setting of KS. METHODS: We describe a unique case of B-cell lymphoma that illustrates histologic features of pediatric-type follicular lymphoma (FL) in a young patient with KS and autoimmune disease who showed a systemic presentation of widespread lymphadenopathy and clonal lymphocytosis. RESULTS: We present the first reported case of a young patient with KS harboring a germline KMT2D variant and presenting with a systemic CD10-positive, BCL2-negative B-cell lymphoma of follicle center origin illustrating histologic features of pediatric-type FL. Targeted next-generation sequencing of the B-cell lymphoma showed somatic TET2 and subclonal CXCR4 variants. These findings suggest that abnormal epigenetic regulation caused by alterations in KMT2D and TET2 may have played critical roles in promoting lymphomagenesis in this patient. CONCLUSIONS: This unique case presentation highlights the importance of close clinical monitoring and the value of clinical context in the diagnosis of pediatric FL-like lesions in patients with KS.
Assuntos
Dioxigenases , Doenças Hematológicas , Linfoma de Células B , Doenças Vestibulares , Criança , Humanos , Epigênese Genética , Doenças Vestibulares/genética , Doenças Vestibulares/complicações , Doenças Vestibulares/diagnóstico , Doenças Hematológicas/complicações , Doenças Hematológicas/genética , Doenças Hematológicas/diagnóstico , Linfoma de Células B/complicações , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Células Germinativas/patologia , Mutação , Proteínas de Ligação a DNA/genética , Dioxigenases/genéticaRESUMO
A number of mammalian genes exhibit the unusual properties of random monoallelic expression and random asynchronous replication. Such exceptional genes include genes subject to X inactivation and autosomal genes including odorant receptors, immunoglobulins, interleukins, pheromone receptors, and p120 catenin. In differentiated cells, random asynchronous replication of interspersed autosomal genes is coordinated at the whole chromosome level, indicative of chromosome-pair non-equivalence. Here we have investigated the replication pattern of the random asynchronously replicating genes in undifferentiated human embryonic stem cells, using fluorescence in situ hybridization based assay. We show that allele-specific replication of X-linked genes and random monoallelic autosomal genes occur in human embryonic stem cells. The direction of replication is coordinated at the whole chromosome level and can cross the centromere, indicating the existence of autosome-pair non-equivalence in human embryonic stem cells. These results suggest that epigenetic mechanism(s) that randomly distinguish between two parental alleles are emerging in the cells of the inner cell mass, the source of human embryonic stem cells.
Assuntos
Cromossomos Humanos , Replicação do DNA , Células-Tronco Embrionárias/citologia , Alelos , Animais , Técnicas de Cocultura , Epigênese Genética , Humanos , Hibridização in Situ Fluorescente , CamundongosRESUMO
Polycomb group proteins are essential for early development in metazoans, but their contributions to human development are not well understood. We have mapped the Polycomb Repressive Complex 2 (PRC2) subunit SUZ12 across the entire nonrepeat portion of the genome in human embryonic stem (ES) cells. We found that SUZ12 is distributed across large portions of over two hundred genes encoding key developmental regulators. These genes are occupied by nucleosomes trimethylated at histone H3K27, are transcriptionally repressed, and contain some of the most highly conserved noncoding elements in the genome. We found that PRC2 target genes are preferentially activated during ES cell differentiation and that the ES cell regulators OCT4, SOX2, and NANOG cooccupy a significant subset of these genes. These results indicate that PRC2 occupies a special set of developmental genes in ES cells that must be repressed to maintain pluripotency and that are poised for activation during ES cell differentiation.
Assuntos
Proteínas de Transporte/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco/fisiologia , Animais , Proteínas de Transporte/genética , Células Cultivadas , Perfilação da Expressão Gênica , Humanos , Complexos Multiproteicos , Proteínas de Neoplasias , Proteínas Nucleares , Análise de Sequência com Séries de Oligonucleotídeos , Complexo Repressor Polycomb 2 , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
The transcription factors OCT4, SOX2, and NANOG have essential roles in early development and are required for the propagation of undifferentiated embryonic stem (ES) cells in culture. To gain insights into transcriptional regulation of human ES cells, we have identified OCT4, SOX2, and NANOG target genes using genome-scale location analysis. We found, surprisingly, that OCT4, SOX2, and NANOG co-occupy a substantial portion of their target genes. These target genes frequently encode transcription factors, many of which are developmentally important homeodomain proteins. Our data also indicate that OCT4, SOX2, and NANOG collaborate to form regulatory circuitry consisting of autoregulatory and feedforward loops. These results provide new insights into the transcriptional regulation of stem cells and reveal how OCT4, SOX2, and NANOG contribute to pluripotency and self-renewal.