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1.
Proc Natl Acad Sci U S A ; 121(18): e2317690121, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38648485

RESUMO

The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies revealed that PML::RARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PML::RARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of PML::RARA, Gata2 overexpression induces many of the same epigenetic and transcriptional changes as PML::RARA. These findings suggested that PML::RARA may indirectly initiate its transcriptional program by activating Gata2 expression: Indeed, we demonstrated that inactivation of Gata2 prior to PML::RARA expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PML::RARA can potentially bind and interact with each other. In turn, PML::RARA binding to DNA promotes a feed-forward transcriptional program by positively regulating Gata2 expression. Gata2 may therefore be required for PML::RARA to establish its transcriptional program.


Assuntos
Fator de Transcrição GATA2 , Células-Tronco Hematopoéticas , Proteínas de Fusão Oncogênica , Animais , Humanos , Camundongos , Sítios de Ligação , Autorrenovação Celular , Cromatina/metabolismo , DNA/metabolismo , Fator de Transcrição GATA2/metabolismo , Fator de Transcrição GATA2/genética , Células-Tronco Hematopoéticas/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Proteínas de Fusão Oncogênica/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteína da Leucemia Promielocítica/metabolismo , Proteína da Leucemia Promielocítica/genética , Ligação Proteica , Receptor alfa de Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/genética
2.
Am J Hum Genet ; 110(5): 846-862, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-37086723

RESUMO

Craniosynostosis (CS) is the most common congenital cranial anomaly. Several Mendelian forms of syndromic CS are well described, but a genetic etiology remains elusive in a substantial fraction of probands. Analysis of exome sequence data from 526 proband-parent trios with syndromic CS identified a marked excess (observed 98, expected 33, p = 4.83 × 10-20) of damaging de novo variants (DNVs) in genes highly intolerant to loss-of-function variation (probability of LoF intolerance > 0.9). 30 probands harbored damaging DNVs in 21 genes that were not previously implicated in CS but are involved in chromatin modification and remodeling (4.7-fold enrichment, p = 1.1 × 10-11). 17 genes had multiple damaging DNVs, and 13 genes (CDK13, NFIX, ADNP, KMT5B, SON, ARID1B, CASK, CHD7, MED13L, PSMD12, POLR2A, CHD3, and SETBP1) surpassed thresholds for genome-wide significance. A recurrent gain-of-function DNV in the retinoic acid receptor alpha (RARA; c.865G>A [p.Gly289Arg]) was identified in two probands with similar CS phenotypes. CS risk genes overlap with those identified for autism and other neurodevelopmental disorders, are highly expressed in cranial neural crest cells, and converge in networks that regulate chromatin modification, gene transcription, and osteoblast differentiation. Our results identify several CS loci and have major implications for genetic testing and counseling.


Assuntos
Craniossinostoses , Tretinoína , Humanos , Mutação , Craniossinostoses/genética , Regulação da Expressão Gênica , Cromatina , Predisposição Genética para Doença
3.
Am J Physiol Cell Physiol ; 326(6): C1735-C1752, 2024 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-38618701

RESUMO

The potential neurotoxic effects of propofol, an extensively utilized anesthetic, underline the urgency to comprehend its influence on neuronal health. Insights into the role of the retinoic acid receptor-α, small nucleolar RNA host gene 1, and brain-derived neurotrophic factor (RARα-Snhg1-Bdnf) network can offer significant advancements in minimizing these effects. The study targets the exploration of the RARα and Snhg1 regulatory network's influence on Bdnf expression in the realm of propofol-induced neurotoxicity. Harnessing the Gene Expression Omnibus (GEO) database and utilizing JASPAR and RNA-Protein Interaction Prediction (RPISeq) database for projections, the study embarks on an in-depth analysis employing both in vitro and in vivo models. The findings draw a clear link between propofol-induced neurotoxicity and the amplification of RAR signaling pathways, impacting hippocampal development and apoptosis and leading to increased RARα and Snhg1 and decreased Bdnf. Propofol is inferred to accentuate neurotoxicity by heightening RARα and Snhg1 interactions, culminating in Bdnf suppression.NEW & NOTEWORTHY This study aimed to decode propofol's neurotoxic effects on the regulatory cascade, provide insights into the RARα-Snhg1-Bdnf interaction, apply extensive validation techniques, provide a detailed analysis and exploration of propofol's neurotoxicity, and offer a comprehensive approach to understanding molecular interactions.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Propofol , Receptor alfa de Ácido Retinoico , Propofol/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Apoptose/efeitos dos fármacos , Masculino
4.
Mol Carcinog ; 63(4): 558-562, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38153216

RESUMO

Acute promyelocytic leukemia (APL) with typically PML::RARA fusion gene caused by t (15;17) (q22; q12) was distinguished from other types of acute myeloid leukemia. In a subset of patients with APL, t (15;17) (q22;q21) and PML::RARA fusion cannot be detected. In this report, we identified the coexistence of STAT3::RARA and RARA::STAT5b fusions for the first time in a variant APL patient lacking t (15;17)(q22;q21)/PML::RARA fusion. Then, this patient was resistant to all-trans retinoic acid combined arsenic trioxide chemotherapy. Accurate detection of RARA gene partners is crucial for variant APL, and effective therapeutic regime is urgently needed.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoína , Fator de Transcrição STAT3/genética
5.
Mol Carcinog ; 63(4): 553-557, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38131515

RESUMO

Acute promyelocytic leukemia (APL) is generally driven by PML::RARA, but approximately 2% of variant APL patients do not contain this fusion gene and pose challenges in diagnosis and treatment. Here, we reported an aggressive APL patient with variant TNRC18::RARA fusion gene, who was resistant to standard differentiation induction therapy consisting of all-trans retinoic acid (ATRA) and arsenic trioxide but achieved complete remission with venetoclax plus ATRA. Mechanistically, venetoclax possesses synergistic effects in ATRA-induced TNRC18::RARA-positive cell differentiation.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
6.
Mod Pathol ; 37(7): 100509, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38704030

RESUMO

Acute promyelocytic leukemia (APL) with variant RARA translocation is linked to over 15 partner genes. Recent publications encompassing 6 cases have expanded the spectrum of RARA partners to torque teno mini virus (TTMV). This entity is likely underrecognized due to the lack of clinician and pathologist familiarity, inability to detect the fusion using routine testing modalities, and informatic challenges in its recognition within next-generation sequencing (NGS) data. We describe a clinicopathologic approach and provide the necessary tools to screen and diagnose APL with TTMV::RARA using existing clinical DNA- or RNA-based NGS assays, which led to the identification of 4 cases, all without other known cytogenetic/molecular drivers. One was identified prospectively and 3 retrospectively, including 2 from custom automated screening of multiple data sets (50,257 cases of hematopoietic malignancy, including 4809 acute myeloid leukemia/myeloid sarcoma/APL cases). Two cases presented as myeloid sarcoma, including 1 with multiple relapses after acute myeloid leukemia-type chemotherapy and hematopoietic stem cell transplant. Two cases presented as leukemia, had a poor response to induction chemotherapy, but achieved remission upon reinduction (including all-trans retinoic acid in 1 case) and subsequent hematopoietic stem cell transplant. Neoplastic cells demonstrated features of APL including frequent azurophilic granules and dim/absent CD34 and HLA-DR expression. RARA rearrangement was not detected by karyotype or fluorescent in situ hybridization. Custom analysis of NGS fusion panel data identified TTMV::RARA rearrangements and, in the prospectively identified case, facilitated monitoring in sequential bone marrow samples. APL with TTMV::RARA is a rare leukemia with a high rate of treatment failure in described cases. The diagnosis should be considered in leukemias with features of APL that lack detectable RARA fusions and other drivers, and may be confirmed by appropriate NGS tests with custom informatics. Incorporation of all-trans retinoic acid may have a role in treatment but requires accurate recognition of the fusion for appropriate classification as APL.


Assuntos
Leucemia Promielocítica Aguda , Proteínas de Fusão Oncogênica , Receptor alfa de Ácido Retinoico , Torque teno virus , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/diagnóstico , Receptor alfa de Ácido Retinoico/genética , Masculino , Torque teno virus/genética , Proteínas de Fusão Oncogênica/genética , Feminino , Adulto , Pessoa de Meia-Idade , Sequenciamento de Nucleotídeos em Larga Escala
7.
Ann Hematol ; 103(4): 1181-1185, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38294534

RESUMO

Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia that is distinguished by the chromosomal translocation t(15;17)(q24;q21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA). Recently, we identified a novel fusion gene in APL, RARA::ankyrin repeat domain 34C (ANKRD34C), identified its functions by morphological, cytogenetic, molecular biological and multiplex fluorescence in situ hybridization analyses, and demonstrated the potential therapeutic effect clinically and experimentally of all-trans retinoic acid (ATRA); the findings have important implications for the diagnosis and treatment of atypical APL.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/tratamento farmacológico , Hibridização in Situ Fluorescente , Tretinoína/uso terapêutico , Receptor alfa de Ácido Retinoico/genética , Proteínas de Transporte/genética , Translocação Genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo
8.
J Cutan Pathol ; 51(6): 419-423, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38468567

RESUMO

Gene fusions have emerged as crucial molecular drivers of oncogenesis in a subset of cutaneous adnexal neoplasms, including poroid neoplasms and hidradenomas. We present a unique case of primary cutaneous apocrine carcinoma harboring RARA::NPEPPS fusion, broadening the spectrum of fusion-associated cutaneous adnexal neoplasms. A 77-year-old African American male presented with an ulcerated thigh nodule. Histopathologically, the predominantly dermal-based adenocarcinoma exhibited papillary, micropapillary, cribriform, and solid growth patterns with central comedonecrosis, set in a fibrotic/desmoplastic stroma. Immunophenotypically, the neoplastic cells were positive for CK7, CK19, GATA3, TRPS1, HER2, CK5/6, calretinin, p63, and DPC4 (no loss), while lacking immunoreactivity for CK20, CDX2, TTF1, napsin-A, PAX8, arginase-1, adipophilin, NKX3.1, uroplakin II, and D2-40. The immunoprofile and clinical and radiographic absence of any internal malignancy, including breast carcinoma, except for multiple lymphadenopathy, supported the diagnosis of primary cutaneous apocrine carcinoma. Next-generation sequencing unveiled the novel RARA::NPEPPS fusion, concurrent ERBB2 amplification, and multiple somatic mutations involving TP53, CDKN2A, BRCA2, PIK3CA, PIK3R1, and others. The patient developed widespread metastases within a year after the initial diagnosis, indicating the tumor's aggressive behavior. This novel fusion, unprecedented in any human malignancies including primary cutaneous adnexal carcinomas, may suggest a potential new subtype within primary cutaneous adnexal carcinoma.


Assuntos
Adenocarcinoma , Proteínas de Fusão Oncogênica , Neoplasias das Glândulas Sudoríparas , Idoso , Humanos , Masculino , Adenocarcinoma/genética , Adenocarcinoma/patologia , Glândulas Apócrinas/patologia , Proteínas de Fusão Oncogênica/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias das Glândulas Sudoríparas/patologia , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/metabolismo
9.
Int J Mol Sci ; 24(17)2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37685882

RESUMO

Cytogenetically cryptic acute promyelocytic leukemia (APL) is rare, characterized by typical clinical and morphological features, but lacks t(15;17)(q24;q21)/PML::RARA translocation seen in conventional karyotyping or FISH. The prompt diagnosis and treatment of APL are critical due to life-threatening complications associated with this disease. However, cryptic APL cases remain a diagnostic challenge that could mislead the appropriate treatment. We describe four cryptic APL cases and review reported cases in the literature. Reverse transcriptase polymerase chain reaction (RT-PCR) is the most efficient diagnostic modality to detect these cases, and alternative methods are also discussed. This study highlights the importance of using parallel testing methods to diagnose cryptic APL cases accurately and effectively.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Cariotipagem
10.
Genes Chromosomes Cancer ; 61(10): 629-634, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35639830

RESUMO

The diagnosis of acute promyelocytic leukemia (APL) relies on the identification of PML::RARA fusion. While the majority of APL cases harbor a typical t(15;17)(q24;q21), atypical genetic mechanisms leading to the oncogenic PML::RARA fusion have been reported yet their frequency and scope remain poorly characterized. We assessed the genetic findings of 831 cases with APL investigated with concurrent chromosome banding analysis and dual-color dual-fusion fluorescence in situ hybridization (D-FISH) analysis at our institution over an 18.5-year timeframe. Seven hundred twenty-three (87%) cases had a typical balanced t(15;17) with both testing modalities. Atypical karyotypic results including complex translocations, unbalanced rearrangements and insertional events occurred in 50 (6%) cases, while 6 (0.7%) cases were cryptic by conventional chromosome studies despite PML::RARA fusion by D-FISH evaluation. Atypical FISH patterns were observed in 48 (6%) cases despite apparently balanced t(15;17) on chromosome banding analysis. Two hundred fifty (30%) cases displayed additional chromosome abnormalities of which trisomy/tetrasomy 8 (37%), del(7q)/add(7q) (12%), and del(9q) (7%) were most frequent. Complex and very complex karyotypes were observed in 81 (10%) and 34 (4%) cases, respectively. In addition, 4 (0.5%) cases presented as an apparently doubled, near-tetraploid stemline clone. This report provides the largest appraisal of cytogenetic findings in APL with conventional chromosome and PML::RARA D-FISH analysis. By characterizing the frequency and breadth of typical and atypical results through the lens of these cytogenetic testing modalities, this study serves as a pragmatic source of information for those involved in the investigation of APL in both the clinical and research laboratory settings.


Assuntos
Leucemia Promielocítica Aguda , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8 , Humanos , Hibridização in Situ Fluorescente , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Estudos Retrospectivos , Translocação Genética , Trissomia
11.
Mol Microbiol ; 115(6): 1122-1137, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33247976

RESUMO

Most, but not all, homologous genetic recombination in bacteria is mediated by the RecA recombinase. The mechanistic origin of RecA-independent recombination has remained enigmatic. Here, we demonstrate that the RarA protein makes a major enzymatic contribution to RecA-independent recombination. In particular, RarA makes substantial contributions to intermolecular recombination and to recombination events involving relatively short (<200 bp) homologous sequences, where RecA-mediated recombination is inefficient. The effects are seen here in plasmid-based recombination assays and in vivo cloning processes. Vestigial levels of recombination remain even when both RecA and RarA are absent. Additional pathways for RecA-independent recombination, possibly mediated by helicases, are suppressed by exonucleases ExoI and RecJ. Translesion DNA polymerases may also contribute. Our results provide additional substance to a previous report of a functional overlap between RecA and RarA.


Assuntos
Adenosina Trifosfatases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Recombinação Homóloga/genética , Recombinases Rec A/genética , Adenosina Trifosfatases/metabolismo , Proteínas de Bactérias/genética , DNA Helicases/metabolismo , Reparo do DNA/genética , DNA Bacteriano/genética , Exodesoxirribonucleases/genética
12.
Cytogenet Genome Res ; 162(6): 306-311, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36724749

RESUMO

Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation t(15;17)(q24;q21), raising two hybrid genes: PML::RARA and RARA::PML. There is a biased clonal evolution in APL since imbalances affecting the der(15) chromosome (the one that carries the transforming PML::RARA gene) have never been reported; instead, imbalances of the der(17), mainly in form of an ider(17)(q10), have been repeatedly documented. We here present two cases with APL who acquired an ider(17)(q10) as a secondary chromosomal change. The presence of the ider(17)(q10) implies several genomic consequences with potential to fuel tumor progression: (1) a duplication of the hybrid gene RARA::PML; (2) a cumulative haploinsufficiency for tumor suppressor genes located in the 17p arm; and (3) a cumulative triplosensitivity of genes located in 17q10→RARA::PML→15qter. Both our patients were treated following the PETHEMA LPA 2012 protocol with ATRA plus idarubicin and they have had a long event-free survival.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/genética , Translocação Genética/genética , Cromossomos , Proteínas de Fusão Oncogênica/genética , Cromossomos Humanos Par 17/genética
13.
Neurobiol Learn Mem ; 191: 107620, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35398514

RESUMO

BACKGROUND: Longitudinal studies reported that some elderly people with normal cognition (NC) converted to mild cognitive impairment (MCI), and some remained normal state (NC_S). The underlying factor for this difference conversion of NC is worthy of exploration METHODS: Eighty-three NC participants were tracked for eight years. Thirty participants transitioned from NC to MCI (NC_MCI). The remaining 53 participants retained an NC_S. The structural brain features and genetic expression of the 83 NC participants were obtained. We applied weighted gene co-expression network analysis (WGCNA) to inquire into the co-expression network of those. Mediator effect analysis of regulatory roles was conducted to inquire into the associations between brain measures, expression values, and clinical scores. RESULTS: The main results are: 1) 20 brain features and 740 gene expression had significant differences between the two groups, 2) one module including 187 genes had the most correlation with cortical thickness of left superior temporal sulcus (L.STS), 3) NFKBIA and RARA genes were the top two genes that made the greatest contribution to L.STS thickness, and 4) mediating effect was found between the L.STS thickness, the NFKBIA and RARA expression levels, and clinical scores. CONCLUSION: Our results provide a theoretical foundation based on gene expression and brain imaging for the factors of NC with different outcomes.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Doença de Alzheimer/genética , Encéfalo/diagnóstico por imagem , Cognição , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Humanos , Imageamento por Ressonância Magnética , Lobo Temporal/diagnóstico por imagem
14.
Rinsho Ketsueki ; 63(11): 1520-1524, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-36476791

RESUMO

We report a case of early asymptomatic acute promyelocytic leukemia (APL) with leukopenia as the only hematologic abnormality. A 55-year-old woman was referred to our hospital with leukopenia (white blood cell [WBC] count of 1,500/µl with 36% neutrophils), which was incidentally determined during an annual medical checkup. Two months before the presentation, her WBC was 3,400/µl with 60% neutrophils. A WBC count was 1,200/µl with 40% neutrophils. Immature myeloid cells were not observed. Her hemoglobin level and platelet count were normal. Moreover, no clinical or laboratory evidence was suggestive of disseminated intravascular coagulation or infection. The peripheral blood WT1 mRNA level was increased to 26,000 copies/µg RNA. The bone marrow aspirate smear revealed 40% myeloperoxidase-positive promyelocytes with occasional Auer rods and faggots; however, circulating leukemia cells were not revealed by cell morphology or flow cytometry analysis. Quantitative reverse-transcription polymerase chain reaction analysis revealed WT1 and PML-RARA fusion transcripts in both the peripheral blood and bone marrow samples. Thus, the determination of peripheral blood WT1 expression may be sufficiently sensitive for detecting a small number of circulating APL cells.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Pessoa de Meia-Idade , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Proteínas WT1/genética
15.
Mol Carcinog ; 60(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33428799

RESUMO

Acute promyelocytic leukemia (APL) is a unique disease entity in acute myeloid leukemia, characterized by PML-RARA fusion gene, which is generated by chromosomal translocation t(15;17)(q24;q21). We identified TNRC18-RARA as novel RARA fusion in resembling APL. Our study highlights the importance of combining multiple molecular techniques to characterize and optimally manage APL lacking classic t(15;17)(q24;q12)/PML-RARA fusion.


Assuntos
Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia Promielocítica Aguda/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Ácido Retinoico/genética , Translocação Genética , Regulação Leucêmica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo
16.
Brain Behav Immun ; 96: 40-53, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33989746

RESUMO

Brain stimulation by electroconvulsive therapy is effective in neuropsychiatric disorders by unknown mechanisms. Microglial toxicity plays key role in neuropsychiatric, neuroinflammatory and degenerative diseases. We examined the mechanism by which electroconvulsive seizures (ECS) regulates microglial phenotype and response to stimuli. Microglial responses were examined by morphological analysis, Iba1 and cytokine expression. ECS did not affect resting microglial phenotype or morphology but regulated their activation by Lipopolysaccharide stimulation. Microglia were isolated after ECS or sham sessions in naïve mice for transcriptome analysis. RNA sequencing identified 141 differentially expressed genes. ECS modulated multiple immune-associated gene families and attenuated neurotoxicity-associated gene expression. Blood brain barrier was examined by injecting Biocytin-TMR tracer. There was no breakdown of the BBB, nor increase in gene-signature of peripheral monocytes, suggesting that ECS effect is mainly on resident microglia. Unbiased analysis of regulatory sequences identified the induction of microglial retinoic acid receptor α (RARα) gene expression and a putative common RARα-binding motif in multiple ECS-upregulated genes. The effects of AM580, a selective RARα agonist on microglial response to LPS was examined in vitro. AM580 prevented LPS-induced cytokine expression and reactive oxygen species production. Chronic murine experimental autoimmune encephalomyelitis (EAE) was utilized to confirm the role RARα signaling as mediator of ECS-induced transcriptional pathway in regulating microglial toxicity. Continuous intracerebroventricular delivery of AM580 attenuated effectively EAE severity. In conclusion, ECS regulates CNS innate immune system responses by activating microglial retinoic acid receptor α pathway, signifying a novel therapeutic approach for chronic neuroinflammatory, neuropsychiatric and neurodegenerative diseases.


Assuntos
Encefalomielite Autoimune Experimental , Microglia , Receptor alfa de Ácido Retinoico , Animais , Eletroconvulsoterapia , Lipopolissacarídeos , Camundongos , Transdução de Sinais
17.
Vnitr Lek ; 67(E-5): 9-12, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35459386

RESUMO

Acute myeloid leukemia (AML) is a highly heterogeneous subtype of leukemia, accounting for 25 % of childhood leukemias. By the presence of genetic mutations in hematopoietic/ progenitor stem cells, the bone marrow produces a large number of abnormal undifferentiated leukocytes (blasts), which significantly impairs the proper differentiation of cells. AML is induced by two interventions. Chromosomal translocation during hematopoiesis of intrauterine development is the first intervention. This creates preleukemic fusion genes (PFG), which can later be transformed by a second intervention (point genetic mutation - deletion, insertion ) into a functional malignant clone. Characteristic AML fusion genes include AML1-ETO, PML-RARA or MLL-AF9, which in turn produce hybrid proteins with altered function. Several studies suggest that these PFGs are considered an important prognostic tool in disease assessment. While the incidence of PFG characteristic of acute lymphoblastic leukemia (ALL) has been relatively well studied by several research groups and has been estimated at 1 to 5% in the umbilical cord blood of healthy neonates, PFG relevant to AML are still not sufficiently clarified.


Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Recém-Nascido , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Prognóstico
18.
Scand J Clin Lab Invest ; 80(2): 87-92, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31829759

RESUMO

Although AML-M3 (APL) and HLA-DR negative non-APL are characterized by negative HLA-DR antigen, they are different entities with similar morphology in some cases. The aim of this study is the precise, differential diagnosis of APL from HLA-DR negative non-APL by flow cytometry to narrow the diagnosis window. Bone marrow or blood samples of 580 AML patients were analyzed, and flow cytometry and molecular analysis were performed for the diagnosis of blood disorders. In 105 HLA-DR negative AML patients, expression of HLA-DR, CD33, CD117, CD11b, CD64, CD34, CD9 and myeloperoxidase staining pattern were evaluated. Fifty-six patients were diagnosed with APL, and 49 patients were diagnosed with HLA-DR negative non-APL. The APL blasts expressed CD33, CD117, CD64, and CD9 in 100%, 80.3%, 94.6%, and 100% of the cases, respectively. HLA-DR negative non-APL blasts expressed CD33, CD117, CD64 and CD9 in 75.5%, 59.1%, 32.6%, and 73.4% of the cases, respectively. APL cells were negative for HLA-DR, CD11b, and CD34 in 96.4%, 94.6%, and 91.0%, respectively. Blasts in HLA-DR negative non M3-AML were negative for CD11b, CD117, and CD34 in 77.5%, 40.9%, and 22.4%, respectively. We also investigated myeloperoxidase (MPO) staining pattern and found strong diffuse reaction in APL cells while HLA-DR negative non-APL cells showed focal positive reaction. In all of the APL patients, except for one, PML/RARA translocation was positive, and in another case with HLA-DR negative non-APL, PML/RARA and other translocations were not detected. The six-panel combination profile rapidly and specifically identifies APL from other HLA-DR negative AML.


Assuntos
Biomarcadores Tumorais/sangue , Citometria de Fluxo/métodos , Antígenos HLA-DR/sangue , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/diagnóstico , Adolescente , Adulto , Antígenos CD34/sangue , Antígeno CD11b/sangue , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Imunofenotipagem , Lactente , Leucemia Promielocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Peroxidase/sangue , Proteínas Proto-Oncogênicas c-kit/sangue , Receptores de IgG/sangue , Tetraspanina 29/sangue , Adulto Jovem
19.
Genes Chromosomes Cancer ; 58(1): 60-65, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30421475

RESUMO

Once the diagnostic suspicion of acute promyelocytic leukemia (APL) has been raised, international guidelines recommend prompt initiation of tailored therapy and supportive care, while awaiting for genetic confirmation of the diagnosis, and the identification of the specific PML/RARA isoform by reverse transcriptase polymerase chain reaction (RT-PCR). Depending on the PML break point, usually located within intron 6, exon 6, or intron 3, different PML/RARA transcript isoforms may be generated, that is, long (bcr1), variant (bcr2), and short (bcr3), respectively. We report here the characterization of three APL cases harboring atypical PML/RARA transcripts, which were not clearly detectable after standard RT-PCR amplification. In all three cases, clinical, morphological, and immunophenotypic features were consistent with APL. Direct sequencing allowed the identification of atypical break points within the PML and RARA genes. Then, we designed a patient-specific quantitative real-time PCR for the atypical transcripts, which allowed for specific quantitative evaluation of minimal residual disease (MRD) during follow-up. Despite the rarity of APL cases with an atypical PML/RARA fusion, our study indicates that an integrated laboratory approach, employing several diagnostic techniques is crucial to timely diagnose APL. This approach allows prompt initiation of specific targeted treatment and reliable MRD monitoring in atypical APL cases.


Assuntos
Leucemia Promielocítica Aguda/genética , Neoplasia Residual/genética , Proteína da Leucemia Promielocítica/genética , Receptor alfa de Ácido Retinoico/genética , Adulto , Idoso , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17 , Éxons/genética , Feminino , Humanos , Íntrons/genética , Cariotipagem , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Proteínas de Fusão Oncogênica/genética
20.
Genes Chromosomes Cancer ; 58(11): 820-823, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31350930

RESUMO

Acute promyelocytic leukemia (APL) is cytogenetically characterized by the t(15;17) (q24;q21), although cases without this translocation exist. These cases are referred to as "cryptic" or "masked" translocations. Additionally, fewer than 5% of APL cases have another partner gene fused to the RARA gene. The TBL1XR1-RARA fusion gene has recently been reported as a novel RARA-associated fusion gene. We report a case with TBL1XR1-RARA and a masked translocation that was not detected by conventional tests for RARA-associated translocations. Three-year-old girl was diagnosed with APL based morphological findings, although conventional tests for RARA-associated chimeric genes were negative. She received all-trans retinoic acid treatment, but that was not effective. She achieved a complete remission (CR) by conventional multidrug chemotherapy, but had extramedullary relapse 2 years after onset. She underwent cord blood transplantation (CBT) in her second CR and is currently alive. To investigate the underlying pathogenesis of this unique case, we performed whole-genome sequencing and found a cryptic insertion of RARA gene into the TBL1XR1 gene. The transcript of the chimeric gene, TBL1XR1-RARA, was confirmed as an in-frame fusion by RT-PCR. In conclusion, we found using next-generation sequencing (NGS) a TBL1XR1-RARA fusion in a child with variant APL without the classic karyotype. Cryptic insertion could also occur in cases other than APL with PML-RARA. Variant APL has many variants and NGS analysis should therefore be considered for APL variant cases, even for those without RARA translocation detected by conventional analysis.


Assuntos
Leucemia Promielocítica Aguda/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Receptor alfa de Ácido Retinoico/genética , Pré-Escolar , Feminino , Fusão Gênica/genética , Humanos , Mutação INDEL/genética , Cariótipo , Cariotipagem , Leucemia Promielocítica Aguda/metabolismo , Proteína da Leucemia Promielocítica/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Repressoras/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Translocação Genética/genética , Sequenciamento Completo do Genoma
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