Functional Genetic Variants in ATG10 Are Associated with Acute Myeloid Leukemia
MetadatosAfficher la notice complète
Acute myeloid leukemiaATG10AutophagySingle nucleotide polymorphism
Castro, I.; Sampaio-Marques, B.; C. Areias, A.; Sousa, H.; Fernandes, Â.; Sanchez-Maldonado, J.M.; Cunha, C.; Carvalho, A.; Sainz, J.; Ludovico, P. Functional Genetic Variants in ATG10 Are Associated with Acute Myeloid Leukemia. Cancers 2021, 13, 1344. [https://doi.org/10.3390/cancers13061344]
PatrocinadorEuropean Commission; Portuguese Foundation for Science and Technology European Commission POCI-01-0145-FEDER-028159 POCI-01-0145-FEDER-030782; Instituto de Salud Carlos III ISCIII-FEDER PI20/01845 ISCIII-FEDER PI12/02688 ISCIII-FEDER PI17/02276; Portuguese Foundation for Science and Technology European Commission POCI-01-0145-FEDER-028159 DL 57/2016 CEECIND/04058/2018 CEECIND/03628/2017
Simple Summary Acute myeloid leukemia (AML) is a hematological neoplasm with a very poor survival rate. To date, diagnostic tools to monitor individuals at higher risk of developing AML are scarce. Single nucleotide polymorphisms (SNPs) have emerged as good candidates for disease prevention. AML is characterized by altered autophagy, a vital mechanism to remove and recycle unnecessary or dysfunctional cellular components. ATG10 is one of the autophagy core genes involved in the autophagosome formation. We hypothesize that SNPs located in regulatory regions of the ATG10 gene could predispose individuals to AML development. We therefore genotyped three SNPs within the ATG10 locus. We identified the ATG10(rs3734114) as a potential risk factor for developing AML, whereas the ATG10(rs1864182) was associated with decreased risk. These findings highlight ATG10 as a key regulator of susceptibility to AML. Furthermore, we believe that ATG10 SNPs could be exploited in the clinical setting as an AML prevention strategy. Acute myeloid leukemia (AML) is the most common acute leukemia, characterized by a heterogeneous genetic landscape contributing, among others, to the occurrence of metabolic reprogramming. Autophagy, a key player on metabolism, plays an essential role in AML. Here, we examined the association of three potentially functional genetic polymorphisms in the ATG10 gene, central for the autophagosome formation. We screened a multicenter cohort involving 309 AML patients and 356 healthy subjects for three ATG10 SNPs: rs1864182T>G, rs1864183C>T and rs3734114T>C. The functional consequences of the ATG10 SNPs in its canonical function were investigated in vitro using peripheral blood mononuclear cells from a cohort of 46 healthy individuals. Logistic regression analysis adjusted for age and gender revealed that patients carrying the ATG10(rs1864182G) allele showed a significantly decreased risk of developing AML (OR [odds ratio] = 0.58, p = 0.001), whereas patients carrying the homozygous ATG10(rs3734114C) allele had a significantly increased risk of developing AML (OR = 2.70, p = 0.004). Functional analysis showed that individuals carrying the ATG10(rs1864182G) allele had decreased autophagy when compared to homozygous major allele carriers. Our results uncover the potential of screening for ATG10 genetic variants in AML prevention strategies, in particular for subjects carrying other AML risk factors such as elderly individuals with clonal hematopoiesis of indeterminate potential.