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1.
Blood ; 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484648

RESUMO

Germline DDX41 mutations are involved in familial myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We analyzed the prevalence and characteristics of DDX41-related myeloid malignancies in an unselected cohort of 1385 patients with MDS or AML. Using targeted next-generation sequencing, we identified 28 different germline DDX41 variants in 43 unrelated patients which we classified as causal (n=21) or unknown significance (n=7) variants. We focused on the 33 patients having causal variants, representing 2.4% of our cohort. Median age was 69 years, most patients were males (79%). Only 9 patients (27%) had a family history of hematological malignancy, while 15 (46%) had personal history of cytopenias years prior to MDS/AML diagnosis. Most patients had normal karyotype (85%) and the most frequent somatic alteration was a second DDX41 mutation (79%). High-risk DDX41 MDS/AML patients treated with intensive chemotherapy (n=9) or azacitidine (n=11) had an overall response rate of 100% and 73%, respectively, with a median overall survival of 5.2 years. Our study highlights that germline DDX41 mutations are relatively common in adult MDS/AML, often without known family history, arguing for systematic screening. Salient features of DDX41-related myeloid malignancies include male preponderance, frequent pre-existing cytopenias, additional somatic DDX41 mutation and relatively good outcome.

3.
Blood ; 133(13): 1495-1506, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30674471

RESUMO

Acute promyelocytic leukemia (APL) is often associated with activating FLT3 signaling mutations. These are highly related to hyperleukocytosis, a major adverse risk factor with chemotherapy-based regimens. APL is a model for oncogene-targeted therapies: all-trans retinoic acid (ATRA) and arsenic both target and degrade its ProMyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARA) driver. The combined ATRA/arsenic regimen now cures virtually all patients with standard-risk APL. Although FLT3-internal tandem duplication (ITD) was an adverse risk factor for historical ATRA/chemotherapy regimens, the molecular bases for this effect remain unknown. Using mouse APL models, we unexpectedly demonstrate that FLT3-ITD severely blunts ATRA response. Remarkably, although the transcriptional output of initial ATRA response is unaffected, ATRA-induced PML/RARA degradation is blunted, as is PML nuclear body reformation and activation of P53 signaling. Critically, the combination of ATRA and arsenic fully rescues therapeutic response in FLT3-ITD APLs, restoring PML/RARA degradation, PML nuclear body reformation, P53 activation, and APL eradication. Moreover, arsenic targeting of normal PML also contributes to APL response in vivo. These unexpected results explain the less favorable outcome of FLT3-ITD APLs with ATRA-based regimens, and stress the key role of PML nuclear bodies in APL eradication by the ATRA/arsenic combination.

5.
Cancer Discov ; 8(12): 1614-1631, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30266814

RESUMO

: Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression. SIGNIFICANCE: The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome-mitochondria axis, suggesting the potential for therapeutic intervention.This article is highlighted in the In This Issue feature, p. 1494.

7.
Blood ; 131(7): 717-732, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29146883

RESUMO

Bone marrow (BM) failure (BMF) in children and young adults is often suspected to be inherited, but in many cases diagnosis remains uncertain. We studied a cohort of 179 patients (from 173 families) with BMF of suspected inherited origin but unresolved diagnosis after medical evaluation and Fanconi anemia exclusion. All patients had cytopenias, and 12.0% presented ≥5% BM blast cells. Median age at genetic evaluation was 11 years; 20.7% of patients were aged ≤2 years and 36.9% were ≥18 years. We analyzed genomic DNA from skin fibroblasts using whole-exome sequencing, and were able to assign a causal or likely causal germ line mutation in 86 patients (48.0%), involving a total of 28 genes. These included genes in familial hematopoietic disorders (GATA2, RUNX1), telomeropathies (TERC, TERT, RTEL1), ribosome disorders (SBDS, DNAJC21, RPL5), and DNA repair deficiency (LIG4). Many patients had an atypical presentation, and the mutated gene was often not clinically suspected. We also found mutations in genes seldom reported in inherited BMF (IBMF), such as SAMD9 and SAMD9L (N = 16 of the 86 patients, 18.6%), MECOM/EVI1 (N = 6, 7.0%), and ERCC6L2 (N = 7, 8.1%), each of which was associated with a distinct natural history; SAMD9 and SAMD9L patients often experienced transient aplasia and monosomy 7, whereas MECOM patients presented early-onset severe aplastic anemia, and ERCC6L2 patients, mild pancytopenia with myelodysplasia. This study broadens the molecular and clinical portrait of IBMF syndromes and sheds light on newly recognized disease entities. Using a high-throughput sequencing screen to implement precision medicine at diagnosis can improve patient management and family counseling.

8.
BMC Med Genet ; 16: 77, 2015 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-26329556

RESUMO

BACKGROUND: Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder characterized by nystagmus, hypotonia, ataxia, progressive spasticity, and cognitive decline. PMD classically results from a duplication of a genomic segment encompassing the entire PLP1 gene. Since the PLP1 gene is located in Xq22, PMD affects mostly boys. METHODS AND RESULTS: Here we report the case of a girl with typical PMD. Copy number analysis of the PLP1 locus revealed a duplication of the entire gene and FISH analysis showed that the extra copy of the PLP1 gene was actually inserted in chromosome 1p36. This insertion of an additional copy of PLP1 in an autosome led to a functional duplication irrespective of the X-inactivation pattern. Subsequent overexpression of PLP1 was the cause of the PMD phenotype observed in this girl. Further sequencing of the breakpoint junction revealed a microhomology and thus suggested a replication based mechanism (such as FoSTeS or MMBIR). CONCLUSION: This case emphasizes the susceptibility of the PLP1 locus to complex rearrangement likely driven by the Xq22 local genomic architecture. In addition, careful consideration should be given to girls with classical PMD clinical features since they usually experience complex PLP1 genomic alteration with a distinct risk of inheritance.


Assuntos
Cromossomos Humanos Par 1/genética , Duplicação Gênica/genética , Mutagênese Insercional/genética , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Imagem por Ressonância Magnética , Análise em Microsséries , Doença de Pelizaeus-Merzbacher/patologia , Inativação do Cromossomo X/genética
9.
J Clin Invest ; 125(9): 3505-18, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26258416

RESUMO

The regulatory microRNA miR-150 is involved in the development of hemopathies and is downregulated in T-lymphomas, such as anaplastic large-cell lymphoma (ALCL) tumors. ALCL is defined by the presence or absence of translocations that activate the anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Here, we compared samples of primary NPM-ALK(+) and NPM-ALK(-) ALCL to investigate the role of miR-150 downstream of NPM-ALK. Methylation of the MIR150 gene was substantially elevated in NPM-ALK(+) biopsies and correlated with reduced miR-150 expression. In NPM-ALK(+) cell lines, DNA hypermethylation-mediated miR-150 repression required ALK-dependent pathways, as ALK inhibition restored miR-150 expression. Moreover, epigenetic silencing of miR-150 was due to the activation of STAT3, a major downstream substrate of NPM-ALK, in cooperation with DNA methyltransferase 1 (DNMT1). Accordingly, miR-150 repression was turned off following treatment with the DNMT inhibitor, decitabine. In murine NPM-ALK(+) xenograft models, miR-150 upregulation induced antineoplastic activity. Treatment of crizotinib-resistant NPM-ALK(+) KARPAS-299-CR06 cells with decitabine or ectopic miR-150 expression reduced viability and growth. Altogether, our results suggest that hypomethylating drugs, alone or in combination with other agents, may benefit ALK(+) patients harboring tumors resistant to crizotinib and other anti-ALK tyrosine kinase inhibitors (TKIs). Moreover, these results support further work on miR-150 in these and other ALK(+) malignancies.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Linfoma Anaplásico de Células Grandes/metabolismo , MicroRNAs/biossíntese , Proteínas Tirosina Quinases/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , RNA Neoplásico/biossíntese , Animais , Linhagem Celular Tumoral , Crizotinibe , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Masculino , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Proteínas Tirosina Quinases/genética , RNA Neoplásico/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
10.
J Hematol Oncol ; 7: 82, 2014 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-25388916

RESUMO

Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated.


Assuntos
Cromossomos Humanos Par 7/genética , Linfoma não Hodgkin/genética , Síndrome de Williams/genética , Criança , Deleção Cromossômica , Hibridização Genômica Comparativa , Feminino , Humanos , Linfoma não Hodgkin/complicações , Masculino , Síndrome de Williams/complicações
11.
Gut ; 62(6): 911-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22942238

RESUMO

BACKGROUND: Metabolic syndrome (MS) is an emerging risk factor in hepatocellular carcinoma (HCC). HCC related to MS may occur either in advanced fibrosis or before the development of cirrhosis, suggesting involvement of different molecular pathways according to the features of background liver. OBJECTIVE: To investigate genomic aberrations in HCC related to MS in order to identify new target genes involved in liver carcinogenesis. METHODS: Chromosomal aberrations of HCC obtained from 20 patients with MS (HCC/MS) were studied by comparative genomic hybridisation and compared with HCC related to hepatitis C virus (HCV) infection (HCC/HCV, n=10) and, within the group of HCC with MS, according to the condition of the background liver (presence or absence of significant fibrosis). RESULTS: Among the most frequent chromosomal alterations observed in HCC, 6p21.1 amplification had a higher incidence in HCC/MS than in HCC/HCV (60% vs 20%, p<0.01). Advanced fibrosis/cirrhosis in the peritumoral liver was the only clinicopathological factor associated with the 6p21.1 amplicon in HCC/MS. Increased expression of cullin7 (CUL7), a gene located at the 6p21.1 locus, was demonstrated in HCC with the 6p21.1 amplicon, in parallel with a decrease in cyclin D1 expression. CUL7 downregulation using siRNA transfection in hepatoma cell lines induced significant cyclin D1 expression (by promoting its degradation), decreased cell proliferation and increased apoptosis. CONCLUSIONS: This study demonstrates specific genomic alterations in HCC/MS and points to CUL7 as a novel gene potentially involved in liver carcinogenesis associated with MS, the amplification of which might influence cell proliferation.


Assuntos
Carcinoma Hepatocelular/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 6/genética , Proteínas Culina/genética , Neoplasias Hepáticas/genética , Síndrome Metabólica/complicações , Idoso , Idoso de 80 Anos ou mais , Apoptose , Western Blotting , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Proliferação de Células , Transformação Celular Neoplásica/genética , Proteínas Culina/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Expressão Gênica , Hepatite C/complicações , Humanos , Imuno-Histoquímica , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase em Tempo Real
12.
Am J Hum Genet ; 91(6): 1135-43, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23217329

RESUMO

Cobblestone lissencephaly is a peculiar brain malformation with characteristic radiological anomalies. It is defined as cortical dysplasia that results when neuroglial overmigration into the arachnoid space forms an extracortical layer that produces agyria and/or a "cobblestone" brain surface and ventricular enlargement. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal-recessive diseases characterized by cerebral, ocular, and muscular deficits. These include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN, and FKRP identified these diseases as alpha-dystroglycanopathies. Our exhaustive screening of these six genes, in a cohort of 90 fetal cases, led to the identification of a mutation in only 53% of the families, suggesting that other genes might also be involved. We therefore decided to perform a genome-wide study in two multiplex families. This allowed us to identify two additional genes: TMEM5 and ISPD. Because TMEM has a glycosyltransferase domain and ISPD has an isoprenoid synthase domain characteristic of nucleotide diP-sugar transferases, these two proteins are thought to be involved in the glycosylation of dystroglycan. Further screening of 40 families with cobblestone lissencephaly identified nonsense and frameshift mutations in another four unrelated cases for each gene, increasing the mutational rate to 64% in our cohort. All these cases displayed a severe phenotype of cobblestone lissencephaly A. TMEM5 mutations were frequently associated with gonadal dysgenesis and neural tube defects, and ISPD mutations were frequently associated with brain vascular anomalies.


Assuntos
Lissencefalia Cobblestone/genética , Proteínas de Membrana/genética , Mutação , Nucleotidiltransferases/genética , Alelos , Lissencefalia Cobblestone/diagnóstico , Consanguinidade , Éxons , Família , Feto/metabolismo , Feto/patologia , Ordem dos Genes , Genótipo , Humanos , Íntrons
13.
Eur J Hum Genet ; 20(5): 527-33, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22234157

RESUMO

In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.


Assuntos
Anormalidades do Olho/genética , Genoma Humano , Adolescente , Adulto , Criança , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Feminino , Fatores de Transcrição Forkhead/genética , Dosagem de Genes , Humanos , Masculino , Fatores de Transcrição Otx/genética , Síndrome
14.
Eur J Hum Genet ; 20(3): 277-82, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21989363

RESUMO

The wide clinical spectrum of the ABCB4 gene (ATP-binding cassette subfamily B member 4) deficiency syndromes in humans includes low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptives-induced cholestasis (CIC), and progressive familial intrahepatic cholestasis type 3 (PFIC3). No ABCB4 mutations are found in a significant proportion of patients with these syndromes. In the present study, 102 unrelated adult patients with LPAC (43 patients) or CIC/ICP (59 patients) were screened for ABCB4 mutations using DNA sequencing. Heterozygous ABCB4 point or short insertion/deletion mutations were found in 37% (16/43) of the LPAC patients and in 27% (16/59) of the ICP/CIC patients. High-resolution gene dosage methodologies were used in the 70 negative patients. Here, we describe for the first time ABCB4 partial or complete heterozygous deletions in 7% (3/43) of the LPAC patients, and in 2% (1/59) of the ICP/CIC patients. Our observations urge to systematically test patients with LPAC, ICP/CIC, and also children with PFIC3 for the presence of ABCB4 deletions using molecular tools allowing detection of gross rearrangements. In clinical practice, a comprehensive ABCB4 alteration-screening algorithm will permit the use of ABCB4 genotyping to confirm the diagnosis of LPAC or ICP/CIC, and allow familial testing. An early diagnosis of these biliary diseases may be beneficial because of the preventive effect of ursodeoxycholic acid on biliary complications. Further comparative studies of patients with well-characterized genotypes (including deletions) and phenotypes will help determine whether ABCB4 mutation types influence clinical outcomes.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Colelitíase/genética , Colestase Intra-Hepática/genética , Anticoncepcionais Orais/efeitos adversos , Doenças da Vesícula Biliar/genética , Deleção de Genes , Complicações na Gravidez/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Adulto , Sequência de Bases , Colestase Intra-Hepática/induzido quimicamente , Cromossomos Humanos Par 7 , Hibridização Genômica Comparativa , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Síndrome , Adulto Jovem
15.
Blood ; 117(15): e161-70, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21325596

RESUMO

Fanconi anemia (FA) is a genetic condition associated with bone marrow (BM) failure, myelodysplasia (MDS), and acute myeloid leukemia (AML). We studied 57 FA patients with hypoplastic or aplastic anemia (n = 20), MDS (n = 18), AML (n = 11), or no BM abnormality (n = 8). BM samples were analyzed by karyotype, high-density DNA arrays with respect to paired fibroblasts, and by selected oncogene sequencing. A specific pattern of chromosomal abnormalities was found in MDS/AML, which included 1q+ (44.8%), 3q+ (41.4%), -7/7q (17.2%), and 11q- (13.8%). Moreover, cryptic RUNX1/AML1 lesions (translocations, deletions, or mutations) were observed for the first time in FA (20.7%). Rare mutations of NRAS, FLT3-ITD, MLL-PTD, ERG amplification, and ZFP36L2-PRDM16 translocation, but no TP53, TET2, CBL, NPM1, and CEBPα mutations were found. Frequent homozygosity regions were related not to somatic copy-neutral loss of heterozygosity but to consanguinity, suggesting that homologous recombination is not a common progression mechanism in FA. Importantly, the RUNX1 and other chromosomal/genomic lesions were found at the MDS/AML stages, except for 1q+, which was found at all stages. These data have implications for staging and therapeutic managing in FA patients, and also to analyze the mechanisms of clonal evolution and oncogenesis in a background of genomic instability and BM failure.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Anemia de Fanconi/genética , Instabilidade Genômica/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Adolescente , Adulto , Medula Óssea/fisiologia , Criança , Pré-Escolar , Anemia de Fanconi/complicações , Feminino , Dosagem de Genes/genética , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Genes Supressores de Tumor , Homozigoto , Humanos , Leucemia Mieloide Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/etiologia , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Blood ; 116(7): 1132-5, 2010 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-20489055

RESUMO

Mutations of the ten eleven translocation 2 gene (TET2) have recently been reported in myelodysplastic syndrome and myeloproliferative neoplasms. We analyzed the incidence and prognostic value of TET2 point mutations and other genomic alterations by direct sequencing and single nucleotide polymorphism microarray analysis in 111 de novo acute myeloid leukemia, who had all achieved complete remission (CR). Mutations were observed in 19 (17%) of the 111 patients compared with 10 (27%) of 36 patients who had failed to achieve CR (P = .2). In the 111 patients who had achieved CR, TET2 alterations were only significantly associated with NPM1 mutations but not with other pretreatment characteristics. TET2 gene status was not significantly correlated with disease-free survival and overall survival, both in the entire cohort and in patients with normal karyotype.


Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Translocação Genética/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Incidência , Cariotipagem , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Adulto Jovem
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