Contributions
Abstract: EP425
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Acute myeloid leukemia (AML) is the most common type of acute leukemia with higher incidence among the elderly population. Furthermore, individuals with genetic predisposition, previous cancer and with an age-related genetic condition, named Clonal Hematopoiesis of Indeterminate Potential (CHIP) are also at a higher risk of developing AML. Thus, finding new tools for monitoring these risk groups would be of great interest for the field. 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, a crucial step in the autophagy process.
Aims
We hypothesize that single nucleotide polymorphisms (SNPs) located in regulatory regions of the ATG10 gene might contribute to the development of this hematological neoplasm. In this study, we examined the association of three potentially functional genetic polymorphisms in the ATG10 gene: rs1864182T>G, rs1864183C>T and rs3734114T>C, with AML.
Methods
A multicenter cohort involving 309 AML patients and 356 healthy subjects for three ATG10 SNPs were screened. The allele frequencies and their association to AML were obtained for the dominant and recessive models adjusted for age and gender. For the three SNPs the Hardy-Weinberg equilibrium was verified. The functional consequences of the ATG10 SNPs in its canonical function were investigated in vitro using peripheral blood mononuclear cells (PBMCs) from a cohort of 46 healthy individuals. Autophagy flux for the most interesting SNPs was performed using gold standard protocols. Informed consent was obtained from all subjects involved in the study.
Results
Logistic regression analysis adjusted for age and gender revealed that patients carrying the ATG10rs1864182G allele showed a significantly decreased risk of developing AML under the dominant model (OR[odds ratio]=0.58, p=0.006), whereas patients carrying the homozygous ATG10rs3734114C allele had a significantly increased risk of AML in the recessive model (OR=of 2.70, p=0.024). We did not find any association between ATG10rs18641823 with AML. Functional analysis showed that individuals carrying the ATG10rs1864182G allele had both decreased levels of ATG10 protein, as well as autophagy flux when compared to homozygous major allele carriers. In particularly, we found a reduced degradation step in the autophagy process when compared with the homozygous major allele group. The correlation between the ATG10rs3734114 SNP and autophagy flux could not be determined due to the low proportion of subjects carrying the homozygous ATG10rs3734114C/C in the healthy cohort, which in agreement with the observed frequency in the European population.
Conclusion
Our results indicate that ATG10 genetic variants show potential clinical implications in AML. Elderly and patients at higher risk could be screened for ATG10rs3734114 to define further monitoring, while our results regarding ATG10rs1864182 suggest a new target that is worth to be further explored in the context of AML.
This research was funded by FEDER and Foundation for Science and Technology (FCT), grant number POCI-01-0145-FEDER-028159 and POCI-01-0145-FEDER-030782); by Fondo de Investigaciones Sanitarias (Madrid, Spain), grant number ISCIII-FEDER PI20/01845, ISCIII-FEDER PI12/02688, and ISCIII-FEDER PI17/02276.
Keyword(s): Acute myeloid leukemia, Single nucleotide polymorphism
Abstract: EP425
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Biology & Translational Research
Background
Acute myeloid leukemia (AML) is the most common type of acute leukemia with higher incidence among the elderly population. Furthermore, individuals with genetic predisposition, previous cancer and with an age-related genetic condition, named Clonal Hematopoiesis of Indeterminate Potential (CHIP) are also at a higher risk of developing AML. Thus, finding new tools for monitoring these risk groups would be of great interest for the field. 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, a crucial step in the autophagy process.
Aims
We hypothesize that single nucleotide polymorphisms (SNPs) located in regulatory regions of the ATG10 gene might contribute to the development of this hematological neoplasm. In this study, we examined the association of three potentially functional genetic polymorphisms in the ATG10 gene: rs1864182T>G, rs1864183C>T and rs3734114T>C, with AML.
Methods
A multicenter cohort involving 309 AML patients and 356 healthy subjects for three ATG10 SNPs were screened. The allele frequencies and their association to AML were obtained for the dominant and recessive models adjusted for age and gender. For the three SNPs the Hardy-Weinberg equilibrium was verified. The functional consequences of the ATG10 SNPs in its canonical function were investigated in vitro using peripheral blood mononuclear cells (PBMCs) from a cohort of 46 healthy individuals. Autophagy flux for the most interesting SNPs was performed using gold standard protocols. Informed consent was obtained from all subjects involved in the study.
Results
Logistic regression analysis adjusted for age and gender revealed that patients carrying the ATG10rs1864182G allele showed a significantly decreased risk of developing AML under the dominant model (OR[odds ratio]=0.58, p=0.006), whereas patients carrying the homozygous ATG10rs3734114C allele had a significantly increased risk of AML in the recessive model (OR=of 2.70, p=0.024). We did not find any association between ATG10rs18641823 with AML. Functional analysis showed that individuals carrying the ATG10rs1864182G allele had both decreased levels of ATG10 protein, as well as autophagy flux when compared to homozygous major allele carriers. In particularly, we found a reduced degradation step in the autophagy process when compared with the homozygous major allele group. The correlation between the ATG10rs3734114 SNP and autophagy flux could not be determined due to the low proportion of subjects carrying the homozygous ATG10rs3734114C/C in the healthy cohort, which in agreement with the observed frequency in the European population.
Conclusion
Our results indicate that ATG10 genetic variants show potential clinical implications in AML. Elderly and patients at higher risk could be screened for ATG10rs3734114 to define further monitoring, while our results regarding ATG10rs1864182 suggest a new target that is worth to be further explored in the context of AML.
This research was funded by FEDER and Foundation for Science and Technology (FCT), grant number POCI-01-0145-FEDER-028159 and POCI-01-0145-FEDER-030782); by Fondo de Investigaciones Sanitarias (Madrid, Spain), grant number ISCIII-FEDER PI20/01845, ISCIII-FEDER PI12/02688, and ISCIII-FEDER PI17/02276.
Keyword(s): Acute myeloid leukemia, Single nucleotide polymorphism