Abstract 7011: The DNA methylation landscape across the TCR loci genes in patients with acute myeloid leukemia
Authors: Mateusz Pospiech, John Beckford, Advaith M. Kumar, Mukund Tamizharasan, Jaqueline Brito, Gangning Liang, Serghei Mangul, Houda Alachkar
Journal: Cancer Research (2024)

Abstract The T-cell receptor (TCR) repertoire is partly shaped by epigenetic modifications, including DNA methylation. Hypomethylating agents like decitabine are used to treat patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The precise DNA methylation patterns within the TCR loci and their dynamics associated with HMAs treatments remain underexplored. Here, we analyzed methylation patterns across TCR alpha and beta gene loci in T cells from GSE175758 and GSE67170 datasets, comparing patterns between patients with AML and healthy controls. We also investigated the impact of decitabine on the methylation patterns of TCR gene loci in patients with AML and MDS (GSE175758 and GSE80762).The overall levels of methylation between T cells from healthy donors and patients with AML were significantly different within the TRAV (0.55 vs 0.42, P &amp;lt; 0.001) and TRBV regions (0.70 vs 0.59, P &amp;lt; 0.001) with 46 TRAV and 33 TRBV sites differentially methylated positions, respectively. However, methylation patterns in HSCs (GSE63409), T cells from healthy donors and patients with AML and those in AML cells were strongly correlated (R &amp;gt; 0.67, range 0.67-0.99, P &amp;lt; 0.001).Because decitabine preferentially acts on leukemic cells and given the high correlation levels between AML cells and T cells across datasets we analyzed the effects of decitabine on TCR DNA methylation patterns in AML cells. In the leukemic cells decitabine treatment led to significant demethylation across 33 and 30 CpG sites within the TRAV and TRBV genes, respectively. In the pre-treatment AML samples higher methylation beta values were observed in differentially methylated positions (DMPs) compared with non-DMPs (TRAV: 0.847 vs 0.407; P &amp;lt; 0.001; TRBV: 0.771 vs 0.538; P = 0.049). In samples largely enriched of myeloid leukemic blasts, we found that TRAV and TRBV loci methylation patterns differ significantly between AML patients with good, moderate, and poor risk patients (P &amp;lt; 0.001). We found TRBV6-1 position 1 and 2 methylation was lower in patients with good risk, compared with intermediate risk (pos1: 0.07 vs 0.13, P=0.04; pos2: 0.1 vs 0.2, P = 0.002) and poor risk (pos 1: 0.07 vs 0.21, P &amp;lt; 0.001; pos 2: 0.1 vs 0.32, P &amp;lt; 0.001) and was lower in patients with intermediate risk compared with poor risk (pos1: 0.13 vs 0.21, p=0.007; pos 2: 0.21 vs 0.32, P = 0.001). The high correlation of TCR DNA methylation patterns between the T cells and the myeloid cells, suggests the need for similar analyses in the context of AML T cells. The study highlights the presence of a conserved TCR loci methylated signatures which is highly correlated between myeloid leukemic cells and T cells and is associated with clinical outcomes, offering a potential avenue for therapeutic intervention. Hypomethylating agents, such as decitabine, can modulate TCR loci methylation patterns. Citation Format: Mateusz Pospiech, John Beckford, Advaith M. Kumar, Mukund Tamizharasan, Jaqueline Brito, Gangning Liang, Serghei Mangul, Houda Alachkar. The DNA methylation landscape across the TCR loci genes in patients with acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7011.