Abstract
Simple SummaryAcute 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 ATG10rs3734114 as a potential risk factor for developing AML, whereas the ATG10rs1864182 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 ATG10rs1864182G allele showed a significantly decreased risk of developing AML (OR [odds ratio] = 0.58, p = 0.001), whereas patients carrying the homozygous ATG10rs3734114C allele had a significantly increased risk of developing AML (OR = 2.70, p = 0.004). Functional analysis showed that individuals carrying the ATG10rs1864182G 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.
Highlights
Acute myeloid leukemia (AML) is the most common acute leukemia in adults with an average age of disease diagnosis above 65 years old [1]
We identified the ATG10rs3734114 as a potential risk factor for developing AML, whereas the ATG10rs1864182 was associated with decreased risk
Gender balance was observed in cohort 1 (χ2 test, p = 0.612), while age distribution was statistically different between AML cases and healthy controls (56 ± 6 and 58 ± 17 years mean age, respectively, p < 0.05)
Summary
Acute myeloid leukemia (AML) is the most common acute leukemia in adults with an average age of disease diagnosis above 65 years old [1]. It is a highly heterogeneous clonal disorder characterized by an impairment in myeloid cellular differentiation and deregulated proliferation, leading to an accumulation of immature myeloid progenitor cells in the bone marrow (BM), peripheral blood, and other tissues. Radiation, or with a genetic predisposition to myeloid neoplasms are at a higher risk of developing AML [2]. It has been reported that individuals presenting an age-related condition named clonal hematopoiesis of indeterminate potential (CHIP), are at higher risk of developing AML. Searching for markers of AML predisposition and progression is of important clinical relevance
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