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Characterisation of an Atrx Conditional Knockout Mouse Model: Atrx Loss Causes Endocrine Dysfunction Rather Than Pancreatic Neuroendocrine Tumour

2022; Multidisciplinary Digital Publishing Institute; Volume: 14; Issue: 16 Linguagem: Inglês

10.3390/cancers14163865

2072-6694

Tiago Bordeira Gaspar, Sofia Macedo, Ana Sá, Mariana Alves Soares, Daniela Ferreira Rodrigues, Mafalda Sousa, Nuno Mendes, Rui Sousa Martins, Luís Cardoso, Inês Borges, Şule Canberk, Fátima Gärtner, Leandro Miranda‐Alves, Manuel Sobrinho‐Simões, José Manuel Lopes, Paula Soares, João Vinagre,

Neuroblastoma Research and Treatments

ATRX is a chromatin remodeller that maintains telomere homeostasis. Loss of ATRX is described in approximately 10% of pancreatic neuroendocrine tumours (PanNETs) and associated with poorer prognostic features. Here, we present a genetically engineered mouse model (GEMM) addressing the role of Atrx loss (AtrxKO) in pancreatic β cells, evaluating a large cohort of ageing mice (for up to 24 months (mo.)). Atrx loss did not cause PanNET formation but rather resulted in worsening of ageing-related pancreatic inflammation and endocrine dysfunction in the first year of life. Histopathological evaluation highlighted an exacerbated prevalence and intensity of pancreatic inflammation, ageing features, and hepatic steatosis in AtrxKO mice. Homozygous floxed mice presented hyperglycaemia, increased weights, and glucose intolerance after 6 months, but alterations in insulinaemia were not detected. Floxed individuals presented an improper growth of their pancreatic endocrine fraction that may explain such an endocrine imbalance. A pilot study of BRACO-19 administration to AtrxKO mice resulted in telomere instability, reinforcing the involvement of Atrx in the maintenance of β cell telomere homeostasis. Thereby, a non-obese dysglycaemic GEMM of disrupted Atrx is here presented as potentially useful for metabolic studies and putative candidate for inserting additional tumourigenic genetic events.