RESUMO
The loss of ß-catenin inhibitory components is a well-established mechanism of carcinogenesis but ß-catenin hyperactivity can also be enhanced through its coactivators. Here we first interrogated a highly validated genomic screen and the largest repository of cancer genomics data and identified JRK as a potential new oncogene and therapeutic target of the ß-catenin pathway. We proceeded to validate the oncogenic role of JRK in colon cancer cells and primary tumors. Consistent with a ß-catenin activator function, depletion of JRK in several cancer cell lines repressed ß-catenin transcriptional activity and reduced cell proliferation. Importantly, JRK expression was aberrantly elevated in 21% of colorectal cancers, 15% of breast and ovarian cancers and was associated with increased expression of ß-catenin target genes and increased cell proliferation. This study shows that JRK is required for ß-catenin hyperactivity regardless of the adenomatous polyposis coli/ß-catenin mutation status and targeting JRK presents new opportunities for therapeutic intervention in cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/genética , Transcrição Gênica , beta Catenina/genética , Transporte Ativo do Núcleo Celular , Sequência de Bases , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células , Neoplasias do Colo/patologia , Simulação por Computador , Proteínas de Ligação a DNA , Feminino , Humanos , Mutação , Proteínas Nucleares/química , Proteínas Nucleares/genética , Oncogenes/genética , Neoplasias Ovarianas/patologia , Domínios Proteicos , Proteínas de Ligação a RNA , Regulação para Cima , Via de Sinalização Wnt/genética , beta Catenina/metabolismoRESUMO
A 6-month-old girl was diagnosed with acute lymphoblastic leukemia (ALL). Chromosome analysis of bone marrow aspirate showed 46,XX,t(4;11)(q21;q23) with an atypical appearance of the 11p on the der(11) chromosome. FISH studies to fully characterize the translocation utilised 8 probes: whole chromosome painting probes for chromosome 11 and chromosome 4; separate chromosome 11 short arm and long arm paints; specific subtelomere probes from 11p, 11q, and 4q; MLL gene probe. Taken together, the results indicated a two-step abnormality: an initial standard t(4;11)(q21;q23), followed by another t(4;11)--this time, between the two derivative chromosomes. The MLL gene was split by the first translocation and its position altered by the second.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 4 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Células da Medula Óssea/patologia , Deleção Cromossômica , Mapeamento Cromossômico , Coloração Cromossômica , Feminino , Variação Genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaAssuntos
Regiões 3' não Traduzidas/genética , Deleção Cromossômica , Inversão Cromossômica/genética , Cromossomos Humanos Par 16/genética , Subunidade beta de Fator de Ligação ao Core/genética , Hibridização in Situ Fluorescente , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto , Humanos , Leucemia Mieloide Aguda/genética , MasculinoRESUMO
The presence of two different abnormal cell lines at diagnosis in hematologic malignancies is rare and raises the question of etiology and pathogenesis--two separate malignant lineages occurring together or a common stem cell malignancy? We present a 64-year-old woman who was evaluated for low platelet count and peripheral blasts. On the basis of the morphology, flow cytometry, and lack of myeloid-associated markers, a diagnosis of precursor B-cell acute lymphoblastic leukemia (B-ALL) was made. Cytogenetic analysis of the diagnostic bone marrow (BM) specimen revealed two unrelated abnormal clones--one had a dicentric (7;9)(p11;p11), resulting in the deletion of 7p and 9p, and the other had only trisomy 8. The dic(7;9) is a rare but recurrent abnormality in B-ALL, while trisomy 8 as a sole abnormality is most commonly associated with myeloid malignancies. After standard treatment for B-ALL, BM cytogenetic analysis showed disappearance of the dic(7;9) cell line but persistence of cells with trisomy 8. The presence of two unrelated clones suggestive of concomitant malignancies, possibly B-ALL with an underlying MDS, may have arisen by different mechanisms.
Assuntos
Leucemia de Células B/genética , Idoso , Bandeamento Cromossômico , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia de Células B/patologiaAssuntos
Estenose Aórtica Supravalvular/genética , Hibridização in Situ Fluorescente , Estenose da Valva Pulmonar/genética , Síndrome de Williams/diagnóstico , Adolescente , Adulto , Estenose Aórtica Supravalvular/congênito , Estenose Aórtica Supravalvular/etiologia , Criança , Pré-Escolar , Feminino , Testes Genéticos/economia , Testes Genéticos/métodos , Humanos , Hibridização in Situ Fluorescente/economia , Hibridização in Situ Fluorescente/estatística & dados numéricos , Lactente , Masculino , Estenose da Valva Pulmonar/congênito , Estenose da Valva Pulmonar/etiologia , Síndrome de Williams/genéticaRESUMO
A 13-year-old girl with an unbalanced karyotype 45,XX,-15,der(22)t(15;22)(q13;q13.3) de novo had Prader-Willi syndrome (PWS), (score 13.5), but with features of mental and physical retardation more severe than usually seen in PWS. The clinical diagnosis of PWS was confirmed by methylation analysis that showed absence of the paternal band. With GTG banding, the cytogenetic breakpoint on chromosome 15q13, with 15q14 intact, encompassed the PWS region, while the breakpoint on 22q was terminal. Investigations with FISH utilised ten different probes/combinations, namely SNRPN/PML, TUPLE1/22q13.3, TUPLE/ARSA, GABRB3, three YAC clones and one cosmid for specific regions within chromosome 15q, painting probes for the long arm of chromosomes 15 and 22 and a pantelomere probe. Deletion of SNRPN,TYAC 9 (at 15q11-12), TYAC19 (at 15q13) and GABRB3 (within the PWS locus), was evident on the derivative (22) chromosome, while TYAC10 (at 15q22), cos15-5 (at 15q22) and PML (15q22) were not deleted. On the der(22), 22q13.3 and ARSA were not deleted, but the most distal non specific pantelomeric probe was deleted. Thus, the severe phenotype could be attributable to deletion on chromosome 15q extending beyond q13 to q14, (further than the usual chromosome 15q deletion (q11-13) in PWS), or be related to loss of the very terminal 22q region (from ARSA to the pantelomere) or be due to genetic factors elsewhere in the genome.