RESUMO
Small supernumerary marker chromosomes (sSMCs) are defined as structurally abnormal chromosomes that are difficult to identify by conventional cytogenetic techniques. sSMCs are 3.75 times more common in infertile men than in the general population. This study aimed at characterizing a supernumerary marker chromosome in a nonconsanguineous infertile couple and analyzing its meiotic segregation in sperm by multicolor FISH. The male partner's karyotype was mos 47,XY,+idic(15)(pterâq11.1::q11.1âpter)[6]/46,XY[24].ish idic(15)(NOR+,D15Z3+,SNRPN-,D15Z3+,NOR+). In triple FISH using CEP 15, BAC 15, and BAC 21 probes, 4,227 spermatozoa of the patient were analyzed, and the sSMC was detected in only 0.66% of spermatozoa. In triple FISH employing CEP X, CEP Y, and BAC 18 probes, 2,008 spermatozoa of the patient were analyzed. The frequency of disomic and diploid sperm was not significantly different from control donors. To our knowledge, segregation of an sSMC 15 has been reported in only 9 males with non-mosaic karyotypes. These studies described rates of spermatozoa with sSMC 15 ranging from 6.23% to more than 50%. In this work, we report the first meiotic segregation analysis of a chromosome 15-derived sSMC in spermatozoa of a patient with a mosaic karyotype. The low rate of spermatozoa with sSMC detected is concordant with the low proportion of abnormal cells in our patient's lymphocytes. Moreover, the risk of interference of this sSMC with other chromosomes seems minimal. Genetic counseling was recommended given that the risk of chromosomal imbalance in the fetus linked to paternal sSMC was very low. Finally, a healthy boy was born after a natural pregnancy.
Assuntos
Cromossomos Humanos Par 15 , Infertilidade , Transtornos Cromossômicos , Segregação de Cromossomos/genética , Feminino , Marcadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Masculino , Gravidez , EspermatozoidesRESUMO
OBJECTIVE/METHOD: 1p36 deletion syndrome is considered to be the most common deletion after 22q11.2 deletion. It is characterized by specific facial features, developmental delay, and organ defects. The primary objective of the present multicenter study was to survey all the cases of 1p36 deletion diagnosed prenatally by French cytogenetics laboratories using a chromosomal microarray. We then compared these new cases with the literature data. RESULTS: Ten new cases were reported. On average, the 1p36 deletion was diagnosed at 19 weeks of gestation. The size of the deletion ranged from 1.6 to 16 Mb. The 1p36 deletion was the only chromosomal abnormality in eight cases and was associated with a complex chromosome 1 rearrangement in the two remaining cases. The invasive diagnostic procedure had always been prompted by abnormal ultrasound findings: elevated nuchal translucency, structural brain abnormality, retrognathia, or a cardiac defect. Multiple anomalies were present in all cases. DISCUSSION: We conclude that 1p36 deletion is not associated with any specific prenatal signs. We suggest that a prenatal observation of ventriculomegaly, congenital heart defect, or facial dysmorphism should prompt the clinician to consider a diagnosis of 1p36 deletion syndrome.
Assuntos
Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adulto , Deleção Cromossômica , Transtornos Cromossômicos/epidemiologia , Cromossomos Humanos Par 1/genética , Feminino , França/epidemiologia , Humanos , Cariotipagem/métodos , Análise em Microsséries/métodos , Gravidez , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/estatística & dados numéricos , Estudos Retrospectivos , Adulto JovemRESUMO
Inv(16)(p13q22) and t(16;16)(p13;q22) are cytogenetic hallmarks of acute myelomonoblastic leukaemia, most of them associated with abnormal bone marrow eosinophils [acute myeloid leukaemia French-American-British classification M4 with eosinophilia (FAB AML-M4Eo)] and a relatively favourable clinical course. They generate a 5'CBFB-3'MYH11 fusion gene. However, in a few cases, although RT-PCR identified a CBFB-MYH11 transcript, normal karyotype and/or fluorescent in situ hybridization (FISH) analyses using commercially available probes are found. We identified a 32-year-old woman with AML-M4Eo and normal karyotype and FISH results. Using two libraries of Bacterial Artificial Chromosome clones on 16p13 and 16q22, FISH analyses identified an insertion of 16q22 material in band 16p13, generating a CBFB-MYH11 type A transcript. Although very rare, insertions should be searched for in patients with discordant cytological and cytogenetic features because of the therapeutic consequences. Copyright © 2015 John Wiley & Sons, Ltd.
Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutagênese Insercional , Proteínas de Fusão Oncogênica/genética , Adulto , Biópsia , Exame de Medula Óssea , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 16 , Feminino , Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Translocação GenéticaRESUMO
Several chromosomal rearrangements involving band 3q26 are known to induce EVI1 overexpression. They include inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22) and t(3;12)(q26;p13). Translocations involving the short arm of chromosome 2 and 3q26 have been reported in more than 50 patients with myeloid disorders. However, although the breakpoints on 2p are scattered over a long segment, their distribution had only been analyzed in 9 patients. We performed fluorescent in situ hybridization with a library of BAC (Bacterial Artificial Chromosome) clones in 4 patients with t(2;3)(p15-23;q26). Our results combined with those of the 9 previously reported patients showed scattering of the breakpoints in 2 regions. A 1.08Mb region in band 2p21 encompassing the MTA3, ZFP36L2 and THADA genes was documented in 5 patients. A second region of 1.83Mb in band 2p16.1 was identified in 8 patients. Four patients showed clustering around the BCL11A gene and the remaining 4 around a long intergenic non-coding RNA, FLJ30838. These regions are characterized by the presence of regulatory sequences (CpG islands and promoters) that could be instrumental in EVI1 overexpression.
Assuntos
Anemia Refratária/genética , Pontos de Quebra do Cromossomo , Proteínas de Ligação a DNA/genética , Heterogeneidade Genética , Leucemia Mieloide Aguda/genética , Proto-Oncogenes/genética , Fatores de Transcrição/genética , Adulto , Idoso , Anemia Refratária/patologia , Inversão Cromossômica , Cromossomos Artificiais Bacterianos , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 3 , Feminino , Expressão Gênica , Biblioteca Gênica , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/patologia , Proteína do Locus do Complexo MDS1 e EVI1 , Masculino , Pessoa de Meia-Idade , Translocação GenéticaRESUMO
T-cell large granular lymphocyte leukemia (LGLL) is a rare clonal disease often associated with rheumatoid arthritis (RA) and manifests chiefly as neutropenia and recurrent infections. Immunosuppressive agents are the mainstay of treatment, but long-term remissions are rare. We report 2 cases of LGLL in patients with RA successfully treated with rituximab, a monoclonal antibody specific of B cells and approved for treating RA. The first patient experienced a complete LGLL remission that was sustained during the 8-year follow-up after the first rituximab infusion. In the second patient, rituximab therapy was followed by immediate neutropenia recovery and then by marked shrinkage of the LGLL clone 1 year later. The paradoxical efficacy of this specific anti-B-cell drug on a monoclonal T-cell disease suggests that some cases of LGLL may be reactive manifestations of chronic autoantigen stimulation rather than true malignancies.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Artrite Reumatoide/terapia , Leucemia Linfocítica Granular Grande/terapia , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/complicações , Feminino , Humanos , Imunoterapia , Leucemia Linfocítica Granular Grande/complicações , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Rituximab , Fatores de Tempo , Resultado do TratamentoRESUMO
The EVI1 gene, located in chromosomal band 3q26, is a transcription factor that has stem cell-specific expression pattern and is essential for the regulation of self-renewal of hematopoietic stem cells. It is now recognized as one of the dominant oncogenes associated with myeloid leukemia. EVI1 overexpression is associated with minimal to no response to chemotherapy and poor clinical outcome. Several chromosomal rearrangements involving band 3q26 are known to induce EVI1 overexpression. They are mainly found in acute myeloid leukemia and blastic phase of Philadelphia chromosome-positive chronic myeloid leukemia, more rarely in myelodysplastic syndromes. They include inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(3;12)(q26;p13) and t(2;3)(p15-23;q26). However, many other chromosomal rearrangements involving 3q26/EVI1 have been identified. The precise molecular event has not been elucidated in the majority of these chromosomal abnormalities and most gene partners remain unknown.
Assuntos
Proteínas de Ligação a DNA/genética , Rearranjo Gênico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Proto-Oncogenes/genética , Fatores de Transcrição/genética , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 3 , Expressão Gênica , Humanos , Proteína do Locus do Complexo MDS1 e EVI1RESUMO
In humans, class I homeobox genes (HOX genes) are distributed in four clusters. Upstream regulators include transcriptional activators and members of the CDX family of transcription factors. HOX genes encode proteins and need cofactor interactions, to increase their specificity and selectivity. HOX genes contribute to the organization and regulation of hematopoiesis by controlling the balance between proliferation and differentiation. Changes in HOX gene expression can be associated with chromosomal rearrangements generating fusion genes, such as those involving MLL and NUP98, or molecular defects, such as mutations in NPM1 and CEBPA for example. Several miRNAs are involved in the control of HOX gene expression and their expression correlates with HOX gene dysregulation. HOX genes dysregulation is a dominant mechanism of leukemic transformation. A better knowledge of their target genes and the mechanisms by which their dysregulated expression contributes to leukemogenesis could lead to the development of new drugs.
Assuntos
Regulação Leucêmica da Expressão Gênica , Genes Homeobox , Leucemia Mieloide Aguda/genética , Animais , Genes Neoplásicos , Humanos , Leucemia Mieloide Aguda/metabolismo , Família Multigênica , Nucleofosmina , Proteínas de Fusão Oncogênica/genéticaRESUMO
Myelodysplastic neoplasms (MDS) are clonal hematopoietic neoplasms. Chromosomal abnormalities (CAs) are detected in 40-45% of de novo MDS and up to 80% of post-cytotoxic therapy MDS (MDS-pCT). Lately, several changes appeared in World Health Organization (WHO) classification and International Consensus Classification (ICC). The novel 'biallelic TP53 inactivation' (also called 'multi-hit TP53') MDS entity requires systematic investigation of TP53 locus (17p13.1). The ICC maintains CA allowing the diagnosis of MDS without dysplasia (del(5q), del(7q), -7 and complex karyotype). Deletion 5q is the only CA, still representing a low blast class of its own, if isolated or associated with one additional CA other than -7 or del(7q) and without multi-hit TP53. It represents one of the most frequent aberrations in adults' MDS, with chromosome 7 aberrations, and trisomy 8. Conversely, translocations are rarer in MDS. In children, del(5q) is very rare while -7 and del(7q) are predominant. Identification of a germline predisposition is key in childhood MDS. Aberrations of chromosomes 5, 7 and 17 are the most frequent in MDS-pCT, grouped in complex karyotypes. Despite the ever-increasing importance of molecular features, cytogenetics remains a major part of diagnosis and prognosis. In 2022, a molecular international prognostic score (IPSS-M) was proposed, combining the prognostic value of mutated genes to the previous scoring parameters (IPSS-R) including cytogenetics, still essential. A karyotype on bone marrow remains mandatory at diagnosis of MDS with complementary molecular analyses now required. Analyses with FISH or other technologies providing similar information can be necessary to complete and help in case of karyotype failure, for doubtful CA, for clonality assessment, and for detection of TP53 deletion to assess TP53 biallelic alterations.
Assuntos
Neoplasias Hematológicas , Síndromes Mielodisplásicas , Adulto , Criança , Humanos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Deleção Cromossômica , Trissomia , Neoplasias Hematológicas/genética , Análise CitogenéticaRESUMO
Bone marrow failure syndromes are rare disorders characterized by bone marrow hypocellularity and resultant peripheral cytopenias. The most frequent form is acquired, so-called aplastic anemia or idiopathic aplastic anemia, an auto-immune disorder frequently associated with paroxysmal nocturnal hemoglobinuria, whereas inherited bone marrow failure syndromes are related to pathogenic germline variants. Among newly identified germline variants, GATA2 deficiency and SAMD9/9L syndromes have a special significance. Other germline variants impacting biological processes, such as DNA repair, telomere biology, and ribosome biogenesis, may cause major syndromes including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome. Bone marrow failure syndromes are at risk of secondary progression towards myeloid neoplasms in the form of myelodysplastic neoplasms or acute myeloid leukemia. Acquired clonal cytogenetic abnormalities may be present before or at the onset of progression; some have prognostic value and/or represent somatic rescue mechanisms in inherited syndromes. On the other hand, the differential diagnosis between aplastic anemia and hypoplastic myelodysplastic neoplasm remains challenging. Here we discuss the value of cytogenetic abnormalities in bone marrow failure syndromes and propose recommendations for cytogenetic diagnosis and follow-up.
Assuntos
Anemia Aplástica , Doenças da Medula Óssea , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Anemia Aplástica/terapia , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea/diagnóstico , Transtornos da Insuficiência da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea/complicações , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Leucemia Mieloide Aguda/complicações , Aberrações Cromossômicas , Análise Citogenética , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
The detection of structural chromosomal abnormalities (SCA) is crucial for diagnosis, prognosis and management of many genetic diseases and cancers. This detection, done by highly qualified medical experts, is tedious and time-consuming. We propose a highly performing and intelligent method to assist cytogeneticists to screen for SCA. Each chromosome is present in two copies that make up a pair of chromosomes. Usually, SCA are present in only one copy of the pair. Convolutional neural networks (CNN) with Siamese architecture are particularly relevant for evaluating similarities between two images, which is why we used this method to detect abnormalities between both chromosomes of a given pair. As a proof-of-concept, we first focused on a deletion occurring on chromosome 5 (del(5q)) observed in hematological malignancies. Using our dataset, we conducted several experiments without and with data augmentation on seven popular CNN models. Overall, performances obtained were very relevant for detecting deletions, particularly with Xception and InceptionResNetV2 models achieving 97.50% and 97.01% of F1-score, respectively. We additionally demonstrated that these models successfully recognized another SCA, inversion inv(3), which is one of the most difficult SCA to detect. The performance improved when the training was applied on inversion inv(3) dataset, achieving 94.82% of F1-score. The technique that we propose in this paper is the first highly performing method based on Siamese architecture that allows the detection of SCA. Our code is publicly available at: https://github.com/MEABECHAR/ChromosomeSiameseAD.
Assuntos
Aberrações Cromossômicas , Doenças Genéticas Inatas , Neoplasias , Redes Neurais de Computação , Humanos , Cromossomos/genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Neoplasias/diagnóstico , Neoplasias/genética , Conjuntos de Dados como AssuntoRESUMO
RNA-Binding Proteins (RBP) are very diverse and cover a large number of functions in the cells. This review focuses on RBM22, a gene encoding an RBP and belonging to the RNA-Binding Motif (RBM) family of genes. RBM22 presents a Zinc Finger like and a Zinc Finger domain, an RNA-Recognition Motif (RRM), and a Proline-Rich domain with a general structure suggesting a fusion of two yeast genes during evolution: Cwc2 and Ecm2. RBM22 is mainly involved in pre-mRNA splicing, playing the essential role of maintaining the conformation of the catalytic core of the spliceosome and acting as a bridge between the catalytic core and other essential protein components of the spliceosome. RBM22 is also involved in gene regulation, and is able to bind DNA, acting as a bona fide transcription factor on a large number of target genes. Undoubtedly due to its wide scope in the regulation of gene expression, RBM22 has been associated with several pathologies and, notably, with the aggressiveness of cancer cells and with the phenotype of a myelodysplastic syndrome. Mutations, enforced expression level, and haploinsufficiency of RBM22 gene are observed in those diseases. RBM22 could represent a potential therapeutic target in specific diseases, and, notably, in cancer.
RESUMO
Myelodysplastic syndromes (MDS) are considered to be diseases associated with splicing defects. A large number of genes involved in the pre-messenger RNA splicing process are mutated in MDS. Deletion of 5q and 7q are of diagnostic value, and those chromosome regions bear the numbers of splicing genes potentially deleted in del(5q) and del(7q)/-7 MDS. In this review, we present the splicing genes already known or suspected to be implicated in MDS pathogenesis. First, we focus on the splicing genes located on chromosome 5 (HNRNPA0, RBM27, RBM22, SLU7, DDX41), chromosome 7 (LUC7L2), and on the SF3B1 gene since both chromosome aberrations and the SF3B1 mutation are the only genetic abnormalities in splicing genes with clear diagnostic values. Then, we present and discuss other splicing genes that are showing a prognostic interest (SRSF2, U2AF1, ZRSR2, U2AF2, and PRPF8). Finally, we discuss the haploinsufficiency of splicing genes, especially from chromosomes 5 and 7, the important amplifier process of splicing defects, and the cumulative and synergistic effect of splicing genes defects in the MDS pathogenesis. At the time, when many authors suggest including the sequencing of some splicing genes to improve the diagnosis and the prognosis of MDS, a better understanding of these cooperative defects is needed.
RESUMO
We question whether, in men with an abnormal rate of sperm DNA fragmentation, the magnetic-activated cell sorting (MACS) could select spermatozoa with lower rates of DNA fragmentation as well as spermatozoa with unbalanced chromosome content. Cryopreserved spermatozoa from six males were separated into nonapoptotic and apoptotic populations. We determined the percentages of spermatozoa with (i) externalization of phosphatidylserine (EPS) by annexin V-Fluorescein isothiocyanate (FITC) labeling, (ii) DNA fragmentation by TdT-mediated-dUTP nick-end labeling (TUNEL), and (iii) numerical abnormalities for chromosomes X, Y, 13, 18, and 21 by fluorescence in situ hybridization (FISH), on the whole ejaculate and selected spermatozoa in the same patient. Compared to the nonapoptotic fraction, the apoptotic fraction statistically showed a higher number of spermatozoa with EPS, with DNA fragmentation, and with numerical chromosomal abnormalities. Compared to the whole ejaculate, we found a significant decrease in the percentage of spermatozoa with EPS and decrease tendencies of the DNA fragmentation rate and the sum of disomy levels in the nonapoptotic fraction. Conversely, we observed statistically significant higher rates of these three parameters in the apoptotic fraction. MACS may help to select spermatozoa with lower rates of DNA fragmentation and unbalanced chromosome content in men with abnormal rates of sperm DNA fragmentation.
Assuntos
Sêmen , Espermatozoides , Anexina A5 , Aberrações Cromossômicas , Fragmentação do DNA , Humanos , Hibridização in Situ Fluorescente , Marcação In Situ das Extremidades Cortadas , Masculino , Projetos PilotoRESUMO
Glioblastomas are frequent malignant brain tumours with a very poor prognosis and a need for new and efficient therapeutic strategies. With the approval of anti-TRK targeted therapies to treat patients with advanced NTRK-rearranged cancers, independent of the type of cancer, potential new treatment opportunities are available for the 0.5-5% of patients with NTRK-rearranged glioblastomas. Identification of these rare NTRK-rearranged glioblastomas requires efficient diagnostic tools and strategies which are evaluated in this study. We compared the results of NTRK1, NTRK2 and NTRK3 fluorescent in situ hybridisation (FISH) assays to those of pan-TRK immunohistochemistry (IHC) using two EPR17341 and A7H6R clones in a set of 196 patients with glioblastomas. Cases with at least 15% of positive nuclei using FISH analyses were further analysed using RNA sequencing. Above the 15% threshold, seven positive glioblastomas (3.57%) were identified by FISH assays (4 NTRK1, 3 NTRK2, no NTRK3). NTRK rearrangements were confirmed by RNA sequencing analyses in four cases [1 LMNA-NTRK1, 1 PRKAR2A-NTRK2, 1 SPECC1L-NTRK2 and 1 NACC2-NTRK2 fusions, i.e., 4/196 (2%) of NTRK-rearranged tumours in our series] but no rearrangement was detected in three samples with less than 30% of positive tumour nuclei as determined by NTRK1 FISH. Pan-TRK immunostaining showed major discrepancies when using either the EPR17341 or the A7H6R clones for the following criteria: main intensity, H-Score based scoring and homogeneity/heterogeneity of staining (Kappa values <0.2). This led to defining adequate criteria to identify NTRK-rearranged gliomas exhibiting strong and diffuse immunostaining contrasting to the variable and heterogeneous staining in non-NTRK-rearranged gliomas (p<0.0001). As assessing NTRK rearrangements has become crucial for glioma therapy, FISH seems to be a valuable tool to maximise access to TRK testing in patients with glioblastomas. In contrast to other cancers, pan-TRK IHC appears of limited interest in this field because there is no 'on/off' IHC positivity criterion to distinguish between NTRK-rearranged and non-NTRK-rearranged gliomas. RNA sequencing analyses are necessary in FISH positive cases with less than 30% positive nuclei, to avoid false positivity when scoring is close to the detection threshold.
Assuntos
Glioblastoma , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Receptores Proteína Tirosina Quinases , Análise de Sequência de RNA , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Feminino , Rearranjo Gênico , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/genética , Receptores Proteína Tirosina Quinases/análise , Receptores Proteína Tirosina Quinases/genética , Receptor trkA/análise , Receptor trkA/genética , Receptor trkC/análise , Receptor trkC/genética , Adulto JovemAssuntos
Cromossomos Humanos Par 13/genética , Leucemia Linfocítica Crônica de Células B/genética , Translocação Genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Deleção de Genes , Humanos , Cariotipagem , Masculino , RNA Longo não Codificante , Transferases , Proteínas Supressoras de Tumor/genéticaRESUMO
We report here three children with a der(11)t(11;16), two sibs (patients 1 and 2) having inherited a recombinant chromosome from a maternal t(11;16)(q24.3;q23.2) and a third unrelated child with a de novo der(11)t(11;16)(q25;q22.1), leading to partial monosomy 11q and trisomy 16q. Fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones and array-CGH were performed to determine the breakpoints involved in the familial and the de novo rearrangements. The partial 11 monosomy extended from 11q24.3 to 11qter and measured 6.17-6.21 Mb in Patients 1 and 2 while the size of the partial 11q25->qter monosomy was estimated at 1.97-2.11 Mb for Patient 3. The partial 16 trisomy extended from 16q23.2 to 16qter and measured 8.93-8.95 Mb in Patients 1 and 2 while the size of the partial 16q22.1->qter trisomy was 20.82 Mb for Patient 3. Intraventricular hemorrhage and transitional thrombocytopenia were found in both sibs but not in the third patient. The FLI1 gene, which is the most relevant gene for thrombocytopenia in Jacobsen syndrome, was neither deleted in family A nor in Patient 3. We suggest that a positional effect could affect the FLI1 expression for these two sibs. Deafness of our three patients confirmed the association of this anomaly to 11q monosomy and tended to confirm the hypothetic role of DFNB20 in Jacobsen syndrome hearing loss. Both sibs shared most of the features commonly observed in Jacobsen syndrome, but not the third patient. This confirmed that terminal 11q trisomy spanning 1 to 1.97-2.11 Mb is not associated with a typical Jacobsen syndrome.
Assuntos
Quebra Cromossômica , Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Síndrome da Deleção Distal 11q de Jacobsen/genética , Trissomia/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 16/genética , Surdez/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariótipo , Masculino , Proteína Proto-Oncogênica c-fli-1/genética , Irmãos , Translocação GenéticaRESUMO
The development of the bacterial artificial chromosome (BAC) system was driven in part by the human genome project in order to construct genomic DNA libraries and physical maps for genomic sequencing. The availability of BAC clones has become a valuable tool for identifying cancer genes. We report here our experience in identifying genes located at breakpoints of chromosomal rearrangements and in defining the size and boundaries of deletions in hematological diseases. The methodology used in our laboratory consists of a three-step approach using conventional cytogenetics followed by FISH with commercial probes, then BAC clones. One limitation to the BAC system is that it can only accommodate inserts of up to 300 kb. As a consequence, analyzing the extent of deletions requires a large amount of material. Array comparative genomic hybridization (array-CGH) using a BAC/PAC system can be an alternative. However, this technique has limitations also, and it cannot be used to identify candidate genes at breakpoints of chromosomal rearrangements such as translocations, insertions, and inversions.
Assuntos
Cromossomos Artificiais Bacterianos , Análise Citogenética/métodos , Leucemia/genética , Pesquisa Biomédica , França , HumanosRESUMO
Chromosomal rearrangements involving the ABL1 gene, leading to a BCR-ABL1 fusion gene, have been mainly associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia (ALL). At present, six other genes have been shown to fuse to ABL1. The kinase domain of ABL1 is retained in all chimeric proteins that are also composed of the N-terminal part of the partner protein that often includes a coiled-coil or a helix-loop-helix domain. These latter domains allow oligomerization of the protein that is required for tyrosine kinase activation, cytoskeletal localization, and neoplastic transformation. Fusion genes that have a break in intron 1 or 2 (BCR-ABL1, ETV6-ABL1, ZMIZ1-ABL1, EML1-ABL1, and NUP214-ABL1) have transforming activity, although NUP214-ABL1 requires amplification to be efficient. The NUP214-ABL1 gene is the second most prevalent fusion gene involving ABL1 in malignant hemopathies, with a frequency of 5% in T-cell ALL. Both fusion genes (SFPQ-ABL1 and RCSD1-ABL1) characterized by a break in intron 4 of ABL1 are associated with B-cell ALL, as the chimeric proteins lacked the SH2 domain of ABL1. Screening for ABL1 chimeric genes could be performed in patients with ALL, more particularly in those with T-cell ALL because ABL1 modulates T-cell development and plays a role in cytoskeletal remodeling processes in T cells.
Assuntos
Genes abl , Neoplasias Hematológicas/genética , Fusão Oncogênica , Transformação Celular Neoplásica/genética , Neoplasias Hematológicas/química , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Oncogênicas v-abl/antagonistas & inibidores , Proteínas Oncogênicas v-abl/química , Proteínas Oncogênicas v-abl/genética , Proteínas de Fusão Oncogênica/genética , Fator de Processamento Associado a PTB , Proteínas Tirosina Quinases/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição/genéticaRESUMO
The RUNX1 gene, located in chromosome 21q22, is crucial for the establishment of definitive hematopoiesis and the generation of hematopoietic stem cells in the embryo. It contains a 'Runt homology domain' as well as transcription activation and inhibition domains. RUNX1 can act as activator or repressor of target gene expression depending upon the large number of transcription factors, coactivators and corepressors that interact with it. Translocations involving chromosomal band 21q22 are regularly identified in leukemia patients. Most of them are associated with a rearrangement of RUNX1. Indeed, at present, 55 partner chromosomal bands have been described but the partner gene has solely been identified in 21 translocations at the molecular level. All the translocations that retain Runt homology domains but remove the transcription activation domain have a leukemogenic effect by acting as dominant negative inhibitors of wild-type RUNX1 in transcription activation.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Fusão Gênica , Neoplasias Hematológicas/genética , Translocação Genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Rearranjo Gênico , Estudos de Associação Genética , HumanosRESUMO
Myelodysplastic syndromes (MDSs) are heterogeneous for their morphology, clinical characteristics, survival of patients, and evolution to acute myeloid leukemia. Different prognostic scoring systems including the International Prognostic Scoring System (IPSS), the Revised IPSS, the WHO Typed Prognostic Scoring System, and the Lower-Risk Prognostic Scoring System have been introduced for categorizing the highly variable clinical outcomes. However, not considered by current MDS prognosis classification systems, gene variants have been identified for their contribution to the clinical heterogeneity of the disease and their impact on the prognosis. Notably, TP53 mutation is independently associated with a higher risk category, resistance to conventional therapies, rapid transformation to leukemia, and a poor outcome. Herein, we discuss the features of monoallelic and biallelic TP53 mutations within MDS, their corresponding carcinogenic mechanisms, their predictive value in current standard treatments including hypomethylating agents, allogeneic hematopoietic stem cell transplantation, and lenalidomide, together with the latest progress in TP53-targeted therapy strategies, especially MDS clinical trial data.