Abstract B017: Dysregulation of ultra long-range DNA methylation canyon interactions in human acute myeloid leukemia

Abstract

Abstract DNA methylation Canyons (DMCs) are genomic regions devoid of DNA methylation over 3.5kb in hematopoietic stem cells (HSCs). DMCs form ultra long-range interactions spanning decades of megabases specifically in HSCs. These ultra-long DMC interactions between DMCs relies on the strong Polycomb binding inside DMC regions. DMCs are hypermethylated and partially activated in cancer. However, its 3D genomic alterations have not been examined extensively. Here we profiled the high-resolution 3D genomic interactions in 7 primary human acute myeloid leukemia (AMLs). Focusing on DMCs' epigenome state, we found that DMCs in all AMLs are hypermethylated and lose the strong Polycomb enrichment within DMCs in comparison with HSC. Based on the DMC interactions, we discovered two subtypes of AMLs with distinct 3D genomic dysregulation of DMCs’ long-range interactions. In the first AML subtype, DMCs’ interactions are still strong as HSPC but gained leukemia-specific long-range interactions. This subtype is enriched for WT1 mutations and is characterized by the expression of CD34 on blast cells. This particular subtype displayed a global basal level increase in the H3K27me3 mark in the genome. This particular subtype of AML is also sensitive to the EZH2 inhibitor treatment. The EZH2 inhibitor treatment leads to the differentiation of blasts and reduces the colony-forming ability of this subtype of AML. Further dissection shows the EZH2 inhibitors could eradicate the leukemia-specific ultra-long range interactions. In the second subtype of AML, 3D genomic interactions between DMCs significantly lost in AMLs with high HOX cluster gene expression (MLL-r and NPM1c+ AMLs). We further found repressive DMC genes, which are developmental transcriptional factors(TFs) in organ formation are activated in these AMLs. Interestingly, these developmental TFs are involved in forming leukemia-specific long-range interactions independent of CTCF-mediated TADs and chromosomal loops. Among those TFs, IRX3 and IRX5 are frequently activated in MLL-r, NPM1c+ AML and MPAL. These two genes have also been shown before to immortalize bone marrow progenitor cells and block differentiation of these progenitor cells. The loci of these two genes form strong long-range connections to an upstream FTO enhancer mimicking the 3D genomic structure observed in developing muscle and brains. Citation Format: Xue Qing D. Wang, Fan Feng, Yali Dou, Jie Liu, Xiaotian Zhang. Dysregulation of ultra long-range DNA methylation canyon interactions in human acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B017.