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1.
Clin Epigenetics ; 16(1): 126, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39261919

RESUMO

DNA-hypomethylating agents (HMAs) induce notable remission rates in AML/MDS patients with TP53 mutations; however, secondary resistance often develops rapidly. In the DECIDER trial (NCT00867672), elderly AML patients (also those with adverse genetics) randomized to all-trans retinoic acid (ATRA) added to decitabine (DEC) attained significantly delayed time-to-resistance. An 82-year-old patient with a non-disruptive, in-frame TP53 mutation (p.Cys238_Asn239delinsTyr, VAF 90%) and complex-monosomal karyotype attained a complete hematologic and cytogenetic remission with DEC + ATRA, with 3.7 years survival after 30 treatment cycles that were well-tolerated. Further HMA + ATRA studies appear warranted in AML/MDS patients of different genetic risk groups ineligible for more intensive treatment.Trial registration: This trial was registered at ClinicalTrials.gov identifier: NCT00867672.


Assuntos
Decitabina , Leucemia Mieloide Aguda , Indução de Remissão , Tretinoína , Proteína Supressora de Tumor p53 , Humanos , Decitabina/uso terapêutico , Decitabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Idoso de 80 Anos ou mais , Tretinoína/uso terapêutico , Indução de Remissão/métodos , Proteína Supressora de Tumor p53/genética , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Cariótipo , Feminino
2.
Blood Adv ; 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39121370

RESUMO

Acute myeloid leukemia (AML) with the t(7;12)(q36;p13) translocation occurs only in very young children and has a poor clinical outcome. The expected oncofusion between breakpoint partners (MNX1 and ETV6) has only been reported in a subset of cases. However, a universal feature is the strong transcript and protein expression of MNX1, a homeobox transcription factor that is normally not expressed in hematopoietic cells. Here, we map the translocation breakpoints on chromosomes 7 and 12 in affected patients to a region proximal to MNX1 and either introns 1 or 2 of ETV6. The frequency of MNX1 overexpression in pediatric AML (n=1556, own and published data) is 2.4% and occurs predominantly in t(7;12)(q36;p13) AML. Chromatin interaction assays in a t(7;12)(q36;p13) iPSC cell line model unravel an enhancer-hijacking event that explains MNX1 overexpression in hematopoietic cells. Our data suggest that enhancer-hijacking may be a more widespread consequence of translocations where no oncofusion product was identified, including e.g. t(1;3) or t(4;12) AML.

3.
Bioinformatics ; 40(6)2024 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-38857451

RESUMO

SUMMARY: The vast amount of publicly available genomic data requires analysis and visualization tools. Here, we present figeno, an application for generating publication-quality FIgures for GENOmics. Figeno particularly focuses on multi-region views across genomic breakpoints and on long reads with base modifications. In addition, we support epigenomic data including ATAC-seq, ChIP-seq or HiC, as well as whole genome sequencing data with copy numbers and structural variants. AVAILABILITY AND IMPLEMENTATION: Figeno is available as a python package with both a command line and graphical user interface. It can be installed via PyPI and the source code is available at https://github.com/CompEpigen/figeno.


Assuntos
Genômica , Software , Genômica/métodos , Humanos , Análise de Sequência de DNA/métodos
4.
Nucleic Acids Res ; 52(10): 5698-5719, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38587186

RESUMO

AT-rich interaction domain protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. Loss of ARID1A leads to DNA repair defects. Here, we show that ARID1A plays epigenetic roles to promote both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates chromatin loops formation by recruiting RAD21 and CTCF to DSBs. Simultaneously, ARID1A facilitates transcription silencing at DSBs in transcriptionally active chromatin by recruiting HDAC1 and RSF1 to control the distribution of activating histone marks, chromatin accessibility, and eviction of RNAPII. ARID1A depletion resulted in enhanced accumulation of micronuclei, activation of cGAS-STING pathway, and an increased expression of immunomodulatory cytokines upon ionizing radiation. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and estimates the levels of tumor-infiltrating immune cells, which can predict the response to the combination of radio- and immunotherapy.


Assuntos
Cromatina , Reparo do DNA , Proteínas de Ligação a DNA , Imunidade , Fatores de Transcrição , Humanos , Linhagem Celular Tumoral , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Recombinação Homóloga/genética , Imunidade/genética , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/imunologia , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Transativadores , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Nat Commun ; 14(1): 4921, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37582954

RESUMO

Reconstructing the history of somatic DNA alterations can help understand the evolution of a tumor and predict its resistance to treatment. Single-cell DNA sequencing (scDNAseq) can be used to investigate clonal heterogeneity and to inform phylogeny reconstruction. However, most existing phylogenetic methods for scDNAseq data are designed either for single nucleotide variants (SNVs) or for large copy number alterations (CNAs), or are not applicable to targeted sequencing. Here, we develop COMPASS, a computational method for inferring the joint phylogeny of SNVs and CNAs from targeted scDNAseq data. We evaluate COMPASS on simulated data and apply it to several datasets including a cohort of 123 patients with acute myeloid leukemia. COMPASS detected clonal CNAs that could be orthogonally validated with bulk data, in addition to subclonal ones that require single-cell resolution, some of which point toward convergent evolution.


Assuntos
Variações do Número de Cópias de DNA , Neoplasias , Humanos , Filogenia , Variações do Número de Cópias de DNA/genética , Algoritmos , Mutação , Neoplasias/genética , Análise de Sequência de DNA , Sequenciamento de Nucleotídeos em Larga Escala
7.
Haematologica ; 108(5): 1259-1271, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-36632736

RESUMO

T-cell acute lymphocytic leukemia protein 1 (TAL1) is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia (T-ALL). Its deregulation can occur through diverse cis-alterations, including SIL-TAL1 microdeletions, translocations with T-cell Receptor loci, and more recently described upstream intergenic non-coding mutations. These mutations consist of recurrent focal microinsertions that create an oncogenic neo-enhancer accompanied by activating epigenetic marks. This observation laid the groundwork for an innovative paradigm concerning the activation of proto-oncogenes via genomic alterations of non-coding intergenic regions. However, for the majority of T-ALL expressing TAL1 (TAL1+), the deregulation mechanism remains 'unresolved'. We took advantage of H3K27ac and H3K4me3 chromatin immunoprecipitation sequencing data of eight cases of T-ALL, including five TAL1+ cases. We identified a putative novel oncogenic neo-enhancer downstream of TAL1 in an unresolved monoallelic TAL1+ case. A rare but recurrent somatic heterozygous microinsertion within this region creates a de novo binding site for MYB transcription factor. Here we demonstrate that this mutation leads to increased enhancer activity, gain of active epigenetic marks, and TAL1 activation via recruitment of MYB. These results highlight the diversity of non-coding mutations that can drive oncogene activation.


Assuntos
Elementos Facilitadores Genéticos , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Proteína 1 de Leucemia Linfocítica Aguda de Células T , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Mutação , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T/genética , Linfócitos T/metabolismo , Fatores de Transcrição/genética
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