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1.
Nat Commun ; 12(1): 4922, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389729

RESUMO

CRISPR-Cas9 is a promising technology for gene therapy. However, the ON-target genotoxicity of CRISPR-Cas9 nuclease due to DNA double-strand breaks has received little attention and is probably underestimated. Here we report that genome editing targeting globin genes induces megabase-scale losses of heterozygosity (LOH) from the globin CRISPR-Cas9 cut-site to the telomere (5.2 Mb). In established lines, CRISPR-Cas9 nuclease induces frequent terminal chromosome 11p truncations and rare copy-neutral LOH. In primary hematopoietic progenitor/stem cells, we detect 1.1% of clones (7/648) with acquired megabase LOH induced by CRISPR-Cas9. In-depth analysis by SNP-array reveals the presence of copy-neutral LOH. This leads to 11p15.5 partial uniparental disomy, comprising two Chr11p15.5 imprinting centers (H19/IGF2:IG-DMR/IC1 and KCNQ1OT1:TSS-DMR/IC2) and impacting H19 and IGF2 expression. While this genotoxicity is a safety concern for CRISPR clinical trials, it is also an opportunity to model copy-neutral-LOH for genetic diseases and cancers.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Globinas/genética , Células-Tronco Hematopoéticas/metabolismo , Perda de Heterozigosidade/genética , Deleção de Sequência , Células Cultivadas , Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Metilação de DNA , Expressão Gênica , Células HEK293 , Células-Tronco Hematopoéticas/citologia , Humanos , Fator de Crescimento Insulin-Like II/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética
2.
Cancer Sci ; 112(9): 3645-3654, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34288263

RESUMO

CD38 expression on myeloma cells is a critical factor affecting the early response to the anti-CD38 antibody daratumumab. However, factors affecting CD38 expression in untreated multiple myeloma are not fully elucidated. In this study, we found that CD38 expression was significantly lower in myeloma patients with the translocation t(11;14)-associated immature plasma cell phenotype, and particularly in those expressing B-cell-associated genes such as PAX5 and CD79A. CD138, a representative marker of plasmacytic differentiation, was also significantly lower in these patients, suggesting that CD38 expression may be associated with the differentiation and maturation stages of myeloma cells. Furthermore, the BCL2/BCL2L1 ratio, a response marker of the BCL2 inhibitor venetoclax, was significantly higher in patients with the immature phenotype expressing B-cell-associated genes. The BCL2/BCL2L1 ratio and CD38 expression were significantly negatively correlated. We also confirmed that patients with translocation t(11;14) expressing B-cell-associated genes were indeed less sensitive to daratumumab-mediated direct cytotoxicity but highly sensitive to venetoclax treatment in ex vivo assays. Moreover, all-trans-retinoic acid, which enhances CD38 expression and induces cell differentiation in myeloma cells, reduced B-cell marker expression and the BCL2/BCL2L1 ratio in myeloma cell lines, leading to reduced efficacy of venetoclax. Venetoclax specifically induces cell death in myeloma with t(11;14), although why patients with translocation t(11;14) show BCL2 dependence is unclear. These results suggest that BCL2 dependence, as well as CD38 expression, are deeply associated with the differentiation and maturation stages of myeloma cells. This study highlights the importance of examining t(11;14) and considering cell maturity in myeloma treatment strategies.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Translocação Genética/genética , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos B/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tretinoína/farmacologia
3.
Nucleic Acids Res ; 49(11): 6315-6330, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34107024

RESUMO

DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.


Assuntos
Síndrome de Beckwith-Wiedemann/genética , Fator de Ligação a CCCTC/metabolismo , Cromossomos Humanos Par 11 , Canal de Potássio KCNQ1/genética , Fator de Ligação a CCCTC/fisiologia , Centrômero , Deleção Cromossômica , Feminino , Impressão Genômica , Humanos , Recém-Nascido , Transcrição Genética
4.
Taiwan J Obstet Gynecol ; 60(3): 540-542, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33966744

RESUMO

OBJECTIVE: We present prenatal diagnosis of trisomy 11 in a single colony of cultured amniocytes at amniocentesis and the perinatal outcome. CASE REPORT: A 36-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+11[1]/46,XX[16]. In 17 colonies of cultured amniocytes, all five cells in one colony had a karyotype of 47,XX,+11, while the rest 16 colonies had a normal karyotype. The parental karyotypes were normal. Repeat amniocentesis was performed at 21 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) was applied on the uncultured amniocytes, and the result revealed 0.9% mosaicism (1/101 cells) for trisomy 11 with only one cell with three signals, while the other 100 cells had two signals, compared with no trisomy 11 signals (0/100 cells) in the normal control. Uniparental disomy (UPD) 11 was excluded by polymorphic DNA marker analysis on the DNAs extracted from uncultured amniocytes and parental bloods. The cultured amniocytes at repeat amniocentesis revealed a karyotype of 46, XX in 28/28 colonies. Prenatal ultrasound findings were unremarkable. The pregnancy was continued to 38 weeks of gestation, and a 2724-g healthy female baby was delivered. The cord blood had a karyotype of 46,XX. The interphase FISH analysis on buccal mucosal cells revealed no trisomy 11 signals (0/100 cells). When follow-up at three months of age, the neonate manifested normal psychomotor and physical development. CONCLUSION: Prenatal diagnosis of mosaic trisomy 11 in a single colony at amniocentesis without abnormal fetal ultrasound and UPD 11 can be associated with a favorable outcome.


Assuntos
Amniocentese , Cromossomos Humanos Par 11/genética , Nascido Vivo/genética , Trissomia/diagnóstico , Adulto , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariótipo , Cariotipagem , Mosaicismo , Gravidez , Trissomia/genética
6.
Int J Legal Med ; 135(4): 1351-1358, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33903958

RESUMO

The Y chromosome is male-specific and is important for spermatogenesis and male fertility. However, the Y chromosome is poorly characterized due to massive palindromes and inverted repeats, which increase the likelihood of genomic rearrangements, resulting in short tandem repeats on the Y chromosome or long fragment deletions. The present study reports a large-scale (2.573~2.648 Mb) deletion in the Yp11.2 region in a Chinese population based on the analysis of 34 selected Y-specific sequence-tagged sites and subsequent sequencing of the breakpoint junctions on the Y chromosome from 5,068,482-5,142,391 bp to 7,715,462-7,716,695 bp. The results of sequence analysis indicated that the deleted region included part or all of the following five genes: PCDH11Y, TSPY, AMELY, TBL1Y, and RKY. These genes are associated with spermatogenesis or amelogenesis and various other processes; however, specific physiological functions and molecular mechanisms of these genes remain unclear. Notably, individuals with this deletion pattern did not have an obvious pathological phenotype but manifested some degree of amelogenesis imperfecta.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Y , Loci Gênicos , Sitios de Sequências Rotuladas , Amelogenina/genética , Caderinas/genética , Proteínas de Ciclo Celular/genética , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 11 , Humanos , Masculino , Repetições de Microssatélites , Transducina/genética
7.
Genes (Basel) ; 12(4)2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923683

RESUMO

Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver-Russell syndrome (SRS), associated with growth restriction, and Beckwith-Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2:intergenic differentially methylated region (H19/IGF2:IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C. However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described.


Assuntos
Impressão Genômica , Herança Materna , Síndrome de Silver-Russell/genética , Dissomia Uniparental/genética , Adolescente , Cromossomos Humanos Par 11/genética , Humanos , Masculino , Mosaicismo , Linhagem , Síndrome de Silver-Russell/diagnóstico , Adulto Jovem
8.
BMC Med Genomics ; 14(1): 99, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836758

RESUMO

BACKGROUND: Potocki-Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome marked by haploinsufficiency of genes in chromosomal region 11p11.2p12. Approximately 50 cases of PSS have been reported; however, a syndrome with a PSS-like clinical phenotype caused by 11p11.12p12 duplication has not yet been reported. METHODS: 11p11.12p12 duplication syndrome was identified and evaluated using a multidisciplinary protocol. Diagnostic studies included intelligence testing, thorough physical examination, electroencephalography (EEG), magnetic resonance imaging (MRI) of the brain, ultrasonography, biochemical tests and karyotype analysis. Next-generation sequencing analysis clarified the location of the chromosomal variations, which was confirmed by chromosome microarray analysis (CMA). Whole-exome sequencing (WES) was performed to exclude single nucleotide variations (SNVs). A wider literature search was performed to evaluate the correlation between the genes contained in the chromosomal region and clinical phenotypes. RESULTS: The proband was a 36-year-old mother with intellectual disability (ID) and craniofacial anomalies (CFA). She and her older son, who had a similar clinical phenotype, both carried the same 11p11.12p12 duplication with a copy number increase of approximately 10.5 Mb (chr11:40231033_50762504, GRCh37/hg19) in chromosome bands 11p11.12p12. In addition, she gave birth to a child with a normal phenotype who did not carry the 11p11.12p12 duplication. By literature research and DECIPHER, we identified some shared and some distinct features between this duplication syndrome and PSS. One or more of ALX4, SLC35C1, PHF21A and MAPK8IP1 may be responsible for 11p11.12p12 duplication syndrome. CONCLUSIONS: We present the first report of 11p11.12p12 duplication syndrome. It is an interesting case worth reporting. The identification of clinical phenotypes will facilitate genetic counselling. A molecular cytogenetic approach was helpful in identifying the genetic aetiology of the patients and potential candidate genes with triplosensitive effects involved in 11p11.12p12 duplication.


Assuntos
Deficiência Intelectual , Adulto , Criança , Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 11 , Exostose Múltipla Hereditária , Feminino , Deleção de Genes , Haploinsuficiência , Humanos , Masculino , Fenótipo
9.
Am J Clin Pathol ; 156(4): 513-520, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-33769443

RESUMO

OBJECTIVES: This study investigates a unique case of multiple osteochondromas (MO) comorbid with enlarged parietal foramina and correlates the findings with the existing literature. The aim of this study is to provide a deeper understanding of anatomic variation for physicians. METHODS: A 66-year-old White male donor was examined during a routine cadaveric dissection performed by medical students in an anatomy laboratory. Detailed exploration of the skeleton and organs was performed, and photographs were taken. Tissue samples were obtained from multiple outgrowths, and histopathologic examination was done. RESULTS: Bilateral bony growths were noted rising from the long bones of the upper and lower extremities (femur, tibia, fibula, and radius). An accessory muscle was found to be associated with the left radial bony growth. Histopathologic examination was positive for osteochondroma. Inspection of the skull revealed enlarged parietal foramina. Other findings included tibiofibular synostosis, abnormally shaped vertebral bodies and ribs, and elongated styloid processes of the skull. CONCLUSIONS: In combination with the histopathologic examination, the case report and literature review elucidate a more precise clinical picture for those affected with MO or similar disorders. This report also emphasizes the necessity of further investigation of the pathogenesis of MO and Potocki-Shaffer syndrome.


Assuntos
Transtornos Cromossômicos/diagnóstico , Encefalocele/diagnóstico , Exostose Múltipla Hereditária/diagnóstico , Ossificação Heterotópica/diagnóstico , Osso Temporal/anormalidades , Idoso , Articulação do Tornozelo/patologia , Deleção Cromossômica , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 11 , Encefalocele/patologia , Exostose Múltipla Hereditária/patologia , Fêmur/patologia , Fíbula/patologia , Humanos , Masculino , Ossificação Heterotópica/patologia , Rádio (Anatomia)/patologia , Osso Temporal/patologia , Tíbia/patologia
10.
Cancer Genet ; 254-255: 92-97, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33647817

RESUMO

The t(1;11)(p32;q23) translocation is a rare but recurrent cytogenetic aberration in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL). This translocation was initially shown to form a fusion gene between KMT2A exon 8 at 11q23 and EPS15 exon 2 at 1p32 in AML. Activating mutations of FLT3 are frequently found in AML but are very rare in ALL. Here, we describe a 75-year-old woman who was diagnosed with B-ALL since her bone marrow was made up of 98.2% lymphoblasts. These blasts were positive for CD19, CD22, CD79a, CD13, and CD33 but negative for CD10 and myeloperoxidase. The karyotype by G-banding and spectral karyotyping was 46,XX,t(1;11)(p32;q23). Expression of KMT2A/EPS15 and reciprocal EPS15/KMT2A fusion transcripts were shown: KMT2A exon 8 was in-frame fused to EPS15 exon 12, indicating that this fusion transcript was a novel type. Considering three reported B-ALL cases, EPS15 breakpoints were markedly different between AML (exon 2) and B-ALL (exons 10-12). Furthermore, an uncommon type of FLT3 mutation in the juxtamembrane domain was detected: in-frame 4-bp deletion and 10-bp insertion. Accordingly, our results indicate that the novel type of KMT2A/EPS15 fusion transcript and FLT3 mutation may cooperate in the pathogenesis of adult B-ALL as class II and class I mutations, respectively.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 1/genética , Mutação/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Translocação Genética , Tirosina Quinase 3 Semelhante a fms/genética , Idoso , Sequência de Aminoácidos , Sequência de Bases , Células da Medula Óssea/patologia , Forma Celular , Evolução Fatal , Feminino , Humanos , Proteínas de Fusão Oncogênica/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tirosina Quinase 3 Semelhante a fms/química
11.
Hum Pathol ; 112: 35-47, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33636207

RESUMO

The most recent World Health Organization classification for skin tumors (2018) categorizes melanomas and their precursor lesions, benign or intermediate, into nine pathways based not only on their clinical and histomorphologic characteristics but also on their molecular profile and genetic fingerprint. In an index case of a partially sampled atypical spitzoid lesion, which proved to be an 11p-amplified Spitz nevus with HRASQ61R mutation, we observed cross-reactivity with the NRASQ61R antibody (clone SP174). Overall, we assessed the status of HRAS and NRAS genes and their immunoreaction to NRASQ61R antibody in 16 cases of 11p-amplified Spitz nevi/atypical Spitz tumors. We also assessed the immunoexpression of NRASQ61R antibody in various malignancies with proven BRAFV600E, NRASQ61R, L or K, KRASQ61R and HRASQ61R, and HRASQ61R mutations and ALK+ Spitz lesions. Finally, we assessed the expression of PReferentially expressed Antigen in MElanoma (PRAME) immunohistochemistry in our 11p Spitz cohort. Three of 16 cases (3/16) harbored the HRASQ61R mutation and exhibited diffuse immunoreaction with the NRASQ61R antibody. All the cases in our cohort were negative for the NRASQ61R mutation. All NRASQ61R-, KRASQ61R-, and HRASQ61R-mutated neoplasms were positive for the antibody, further supporting the cross-reactivity between the RAS proteins. All the cases of our cohort were essentially negative for PRAME immunohistochemistry. In the era of pathway-based approach in the diagnosis of melanocytic neoplasms, the cross-reactivity between the NRASQ61R- and HRASQ61R-mutated proteins can lead to a diagnostic pitfall in the assessment of lesions with spitzoid characteristics.


Assuntos
Anticorpos Monoclonais/imunologia , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Nevo de Células Epitelioides e Fusiformes/diagnóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Cutâneas/diagnóstico , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Criança , Cromossomos Humanos Par 11 , Reações Cruzadas , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/genética , Pessoa de Meia-Idade , Mutação , Nevo de Células Epitelioides e Fusiformes/genética , Neoplasias Cutâneas/genética , Adulto Jovem
13.
Int J Biol Macromol ; 176: 437-447, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33592266

RESUMO

TFE3 gene fusions often place TFE3 under the control of a more active promoter and cause overexpression of the TFE3 proteins in renal cell carcinoma associated with Xp11.2 translocations (Xp11.2 tRCC). The purpose of this study was to investigate the transcriptional regulation and aggregation mechanism of NONO-TFE3 in NONO-TFE3 tRCC. In this study, we found that the nuclear aggregation of NONO-TFE3 fusion was significantly more than that of intact TFE3 or PRCC-TFE3 fusion. We observed that NONO fragment mediated-phase separation promoted stabilization and aggregation of NONO-TFE3 fusion. Meantime, we revealed that the positive regulation loop between NONO-TFE3 and NRF1 increased mitochondrial biosynthesis and metabolism in NONO-TFE3 tRCC. Therefore, the present study raises the possibility that mitochondrial metabolism is potentially a fruitful arena for NONO-TFE3 tRCC therapy.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma de Células Renais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fator 1 Nuclear Respiratório/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Agregados Proteicos , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 11/metabolismo , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fator 1 Nuclear Respiratório/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a RNA/genética , Translocação Genética
14.
Leukemia ; 35(8): 2232-2242, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33542481

RESUMO

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 4/genética , Proteínas de Ligação a DNA/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Fatores de Elongação da Transcrição/genética , Adulto , Proteínas de Ligação a DNA/metabolismo , Feminino , Seguimentos , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Masculino , Proteína de Leucina Linfoide-Mieloide/metabolismo , Neoplasia Residual/genética , Neoplasia Residual/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Elongação da Transcrição/metabolismo , Translocação Genética , Condicionamento Pré-Transplante , Transplante Homólogo
15.
Cell Prolif ; 54(2): e12978, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33393114

RESUMO

OBJECTIVES: The final stage of liver development is the production of hepatocytes and cholangiocytes (biliary epithelial cells) from bipotent hepatic progenitor cells. We used HepaRG cells, which are bipotent and able to differentiate into both hepatocytes and cholangiocytes, as a model to study the action of a novel lncRNA (lnc-RHL) and its role in the regulation of bipotency leading to hepatocytes and cholangiocytes. MATERIALS AND METHODS: Differentiation of HepaRG cells was assessed by marker expression and morphology which revealed their ability to differentiate into hepatocytes and cholangiocytes (modelling the behaviour of hepatoblasts in vivo). Using a qRT-PCR and RACE, we cloned a novel lncRNA (lnc-RHL; regulator of hepatic lineages) that is upregulated upon HepaRG differentiation. Using inducible knockdown of lnc-RHL concurrently with differentiation, we show that lnc-RHL is required for proper HepaRG cell differentiation resulting in diminution of the hepatocyte lineage. RESULTS: Here, we report the discovery of lnc-RHL, a spliced and polyadenylated 670 base lncRNA expressed from the 11q23.3 apolipoprotein gene cluster. lnc-RHL expression is confined to hepatic lineages and is upregulated when bipotent HepaRG cells are caused to differentiate. HepaRG cells made deficient for lnc-RHL have reduced ability to differentiate into hepatocytes, but retain their ability to differentiate into cholangiocytes. CONCLUSIONS: Deficiency for lnc-RHL in HepaRG cells converts them from bipotent progenitor cells to unipotent progenitor cells with impaired ability to yield hepatocytes. We conclude that lnc-RHL is a key regulator of bipotency in HepaRG cells.


Assuntos
Diferenciação Celular/genética , Hepatócitos/metabolismo , RNA Longo não Codificante/metabolismo , Apolipoproteínas/genética , Apolipoproteínas/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula , Criança , Cromossomos Humanos Par 11 , Doxorrubicina/farmacologia , Feminino , Células Hep G2 , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/citologia , Humanos , Fígado/metabolismo , Masculino , Família Multigênica , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Adulto Jovem
16.
Am J Surg Pathol ; 45(2): 277-285, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33428338

RESUMO

A subset of Spitz tumors is associated with a copy number increase of chromosome 11p and activating mutations of HRAS. These aberrations have been reported to occur in association with desmoplastic Spitz nevi. Little is known to what extent 11p gains can also be found in nondesmoplastic tumors. To learn more about the spectrum of microscopic and cytogenetic changes that can be seen in Spitz lesions in association with 11p gains, we reviewed the clinical and pathologic features of 40 cases. Patient ages ranged from 3 to 75 years. The most common anatomic site was the head and neck region, followed by the upper extremities. Prominent desmoplasia was present in 10 cases. Seven tumors lacked significant stromal fibrosis. Twenty tumors were mitotically active. Novel microscopic features encountered in a few cases include a tumor with a polypoid silhouette and papillomatous surface and rare atypical tumors with a deep bulbous growth pattern. Among 36 cases analyzed by single-nucleotide polymorphism array or comparative genomic hybridization, 28 tumors had gains of the entire or near-entire p-arm of chromosome 11 with no other coexisting unbalanced genomic aberration. Eight cases had additional changes; 6 of these with 1 additional aberration per case, and 2 cases had several chromosomal aberrations. We also examined a subset of tumors by fluorescence in situ hybridization for the HRAS gene locus (11p15.5). All tumors were fluorescence in situ hybridization-positive. In conclusion, we expand the spectrum of pathologic findings associated with Spitz tumors with 11p gains. This cytogenetic aberration is not restricted to desmoplastic Spitz nevi. It can also be seen in nondesmoplastic and papillomatous lesions and atypical melanocytic tumors with a deep bulbous growth. We also document that in some Spitz tumors additional cytogenetic aberrations may be found, the significance of which remains to be determined.


Assuntos
Cromossomos Humanos Par 11/genética , Nevo de Células Epitelioides e Fusiformes/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Aberrações Cromossômicas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nevo de Células Epitelioides e Fusiformes/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Cutâneas/patologia , Adulto Jovem
17.
Cancer Genomics Proteomics ; 18(1): 67-81, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33419897

RESUMO

BACKGROUND/AIM: Fusion of histone-lysine N-methyltransferase 2A gene (KMT2A) with the Rho guanine nucleotide exchange factor 12 gene (ARHGEF12), both located in 11q23, was reported in some leukemic patients. We report a KMT2A-ARHGEF12 fusion occurring during treatment of a pediatric acute myeloid leukemia (AML) with topoisomerase II inhibitors leading to a secondary acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: Multiple genetic analyses were performed on bone marrow cells of a girl initially diagnosed with AML. RESULTS: At the time of diagnosis with AML, the t(9;11)(p21;q23)/KMT2A-MLLT3 genetic abnormality was found. After chemotherapy resulting in AML clinical remission, a 2 Mb deletion in 11q23 was found generating a KMT2A-ARHGEF12 fusion gene. When the patient later developed B lineage ALL, a t(14;19)(q32;q13), loss of one chromosome 9, and KMT2A-ARHGEF12 were detected. CONCLUSION: The patient sequentially developed AML and ALL with three leukemia-specific genomic abnormalities in her bone marrow cells, two of which were KMT2A-rearrangements.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Cromossomos Humanos Par 11 , Feminino , Deleção de Genes , Fusão Gênica , Fatores de Troca do Nucleotídeo Guanina/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Leucemia Mieloide Aguda/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
18.
J Clin Oncol ; 39(7): 704-712, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33492986

RESUMO

PURPOSE: As yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy. PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Among all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1- patients, respectively (P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7% (P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab. CONCLUSION: The POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Recidiva Local de Neoplasia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , China , Cromossomos Humanos Par 11 , DNA Viral/genética , Progressão da Doença , Feminino , Herpesvirus Humano 4/genética , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/secundário , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Intervalo Livre de Progressão , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Fatores de Tempo , Carga Viral , Adulto Jovem
19.
Taiwan J Obstet Gynecol ; 60(1): 169-172, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33494996

RESUMO

OBJECTIVE: We present tetrasomy of 11q13.4-q14.3 due to an intrachromosomal triplication associated with paternal isodisomy of uniparental disomy (iso-UPD) for 11q14.3-qter and multiple abnormalities. CASE REPORT: A 30-year-old primigravid woman was found to have intrauterine growth restriction (IUGR) in the fetus since 28 weeks of gestation, and a 2056-g baby was delivered at 38 weeks of gestation with fetal distress. The baby postnatally manifested hypotonia, microcephaly, facial dysmorphism of micrognathia, retrognathia and low-set ears, ventricular septal defect, atrial septal defect, tricuspid regurgitation and corpus callosum dysgenesis. A single nucleotide polymorphism (SNP) array comparative genomic hybridization analysis on the DNA extracted from the peripheral blood revealed the result of arr 11q13.4q14.3 (71,567,724-89,547,851) × 4, arr 11q14.3q25 (89,466,484-134,942,626) hmz [GRCh37 (hg19)] with a 17.980-Mb triplication of 11q13.4-q14.3 encompassing the genes of GRM5 and MAP6, and loss of heterozygosity for a 45.476-Mb region of 11q14.3-qter consistent with iso-UPD for 11q14.3-qter. Polymorphic DNA marker analysis confirmed paternal iso-UPD for 11q14.3-qter. Cytogenetic analysis of the blood revealed a karyotype of 46,XY,trp(11) (q13.4q14.3). The parental karyotypes were normal. When follow-ups at age 2 years, the neonate manifested physical and psychomotor developmental delay and intellectual disability. CONCLUSION: Tetrasomy 11q13.4-q14.3 may present the phenotype of IUGR, developmental delay, corpus callosum dysgenesis, microcephaly, congenital heart defects and facial dysmorphism.


Assuntos
Cromossomos Humanos Par 11/genética , Herança Paterna/genética , Tetrassomia/genética , Trissomia/genética , Dissomia Uniparental/genética , Anormalidades Múltiplas/genética , Adulto , Agenesia do Corpo Caloso/genética , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/genética , Análise Citogenética , Deficiências do Desenvolvimento/genética , Feminino , Retardo do Crescimento Fetal/genética , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Deficiência Intelectual/genética , Microcefalia/genética , Atrofia Muscular/genética , Fenótipo , Gravidez
20.
J Pediatr Hematol Oncol ; 43(3): e371-e374, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32134839

RESUMO

KMT2A gene rearrangements represent the most frequent group of abnormalities in childhood leukemia (~70% of cases), with over 120 rearrangements described. The investigation of KMT2A rearrangements is still a vast field to be explored. Several studies have been characterizing different outcomes and leukemogenic mechanisms, depending on the translocation partner gene involved in childhood KMT2A-r leukemias. Therefore, the detection of the translocation partner gene, including in the context of complex rearrangements, may help to better delineate the disease. Here, we describe clinical and molecular cytogenetic data of a new complex variant translocation, involving chromosomes 9, 11, and 14, presenting a KMT2A gene extra copy and rearrangements, in an infant with de novo mixed-phenotype acute leukemia.


Assuntos
Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Leucemia Aguda Bifenotípica/genética , Proteína de Leucina Linfoide-Mieloide/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 9 , Citogenética , Dosagem de Genes , Humanos , Lactente , Masculino
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