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1.
Blood ; 143(20): 2059-2072, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38437498

RESUMO

ABSTRACT: BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as a promising therapy for AML with MLL1r or mtNPM1.


Assuntos
DNA Helicases , Leucemia Mieloide Aguda , Proteínas Nucleares , Proteínas Proto-Oncogênicas , Fatores de Transcrição , Animais , Humanos , Camundongos , Proteínas que Contêm Bromodomínio , Linhagem Celular Tumoral , DNA Helicases/antagonistas & inibidores , DNA Helicases/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Mol Cell Biol ; 25(24): 11184-90, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16314537

RESUMO

Imprinted methylation of the paternal Rasgrf1 allele in mice occurs at a differentially methylated domain (DMD) 30 kbp 5' of the promoter. A repeated sequence 3' of the DMD regulates imprinted methylation, which is required for imprinted expression. Here we identify the mechanism by which methylation controls imprinting. The DMD is an enhancer blocker that binds CTCF in a methylation-sensitive manner. CTCF bound to the unmethylated maternal allele silences expression. CTCF binding to the paternal allele is prevented by repeat-mediated methylation, allowing expression. Optimal in vitro enhancer-blocking activity requires CTCF binding sites. The enhancer blocker can be bypassed in vivo and imprinting abolished by placing an extra enhancer proximal to the promoter. Together, the repeats and the DMD constitute a binary switch that regulates Rasgrf1 imprinting.


Assuntos
Proteínas de Transporte/genética , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos/genética , Impressão Genômica , Proteínas Repressoras/metabolismo , Animais , Fator de Ligação a CCCTC , Proteínas Ativadoras de GTPase , Camundongos , Modelos Genéticos
3.
Cancer Discov ; 7(9): 1030-1045, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28526733

RESUMO

Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell-cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody-drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models-a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030-45. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 920.


Assuntos
Antineoplásicos/uso terapêutico , Caderinas/antagonistas & inibidores , Neoplasias Renais/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Caderinas/genética , Caderinas/metabolismo , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Macaca fascicularis , Camundongos Nus , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Proc Natl Acad Sci U S A ; 103(34): 12763-8, 2006 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-16908844

RESUMO

Dorsal-ventral (DV) patterning of the Drosophila embryo is initiated by Dorsal, a sequence-specific transcription factor distributed in a broad nuclear gradient in the precellular embryo. Previous studies have identified as many as 70 protein-coding genes and one microRNA (miRNA) gene that are directly or indirectly regulated by this gradient. A gene regulation network, or circuit diagram, including the functional interconnections among 40 Dorsal target genes and 20 associated tissue-specific enhancers, has been determined for the initial stages of gastrulation. Here, we attempt to extend this analysis by identifying additional DV patterning genes using a recently developed whole-genome tiling array. This analysis led to the identification of another 30 protein-coding genes, including the Drosophila homolog of Idax, an inhibitor of Wnt signaling. In addition, remote 5' exons were identified for at least 10 of the approximately 100 protein-coding genes that were missed in earlier annotations. As many as nine intergenic uncharacterized transcription units were identified, including two that contain known microRNAs, miR-1 and -9a. We discuss the potential functions of these recently identified genes and suggest that intronic enhancers are a common feature of the DV gene network.


Assuntos
Padronização Corporal/genética , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Genoma de Inseto/genética , Análise de Sequência com Séries de Oligonucleotídeos , Animais , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo
5.
Genes Dev ; 19(24): 2947-52, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16357215

RESUMO

The Drosophila Bithorax Complex encodes three well-characterized homeodomain proteins that direct segment identity, as well as several noncoding RNAs of unknown function. Here, we analyze the iab-4 locus, which produces the microRNAs iab-4-5p and iab-4-3p. iab-4 is analogous to miR-196 in vertebrate Hox clusters. Previous studies demonstrate that miR-196 interacts with the Hoxb8 3' untranslated region. Evidence is presented that miR-iab-4-5p directly inhibits Ubx activity in vivo. Ectopic expression of mir-iab-4-5p attenuates endogenous Ubx protein accumulation and induces a classical homeotic mutant phenotype: the transformation of halteres into wings. These findings provide the first evidence for a noncoding homeotic gene and raise the possibility that other such genes occur within the Bithorax complex. We also discuss the regulation of mir-iab-4 expression during development.


Assuntos
Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Genes de Insetos/fisiologia , Proteínas de Homeodomínio/metabolismo , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismo , Asas de Animais/embriologia , Regiões 3' não Traduzidas/genética , Animais , Drosophila , Proteínas de Homeodomínio/genética , MicroRNAs/genética , Família Multigênica/fisiologia , Mutação
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