RT Journal Article SR Electronic T1 Three-dimensional Genome Organization Maps in Normal Haematopoietic Stem Cells and Acute Myeloid Leukemia JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.04.18.047738 DO 10.1101/2020.04.18.047738 A1 Benny Wang A1 Lingshi Kong A1 Deepak Babu A1 Ruchi Choudhary A1 Winnie Fam A1 Jia Qi Tng A1 Yufen Goh A1 Xin Liu A1 Fang Fang Song A1 Priscella Chia A1 Ming Chun Chan A1 Omer An A1 Cheng Yong Tham A1 Touati Benoukraf A1 Henry Yang A1 Wilson Wang A1 Wee Joo Chng A1 Daniel Tenen A1 Melissa Jane Fullwood YR 2020 UL http://biorxiv.org/content/early/2020/04/18/2020.04.18.047738.abstract AB Acute Myeloid Leukemia (AML) is a highly lethal blood cancer arising due to aberrant differentiation of haematopoietic stem cells. MEIS1 and HOXA9 regulate stemness-related transcriptional programs in normal haematopoietic stem cells and AML. Here we obtained 3D genome organization maps in the CD34+ haematopoietic stem cells from 3 healthy individuals and 3 individuals with AML. The MEIS1 oncogenic transcription factor is regulated by a Frequently Interacting Region (FIRE). This FIRE is present in normal bone marrow samples, and an AML sample with high MEIS1 levels. However, it is absent in two AML samples that show low MEIS1 levels. CRISPR excision of the FIRE led to loss of MEIS1 and reduced cell growth. Moreover, MEIS1 can bind to the promoter of HOXA9, and HOXA9 can also auto-regulate by binding to its own promoter as well as an Acute Myeloid Leukemia-specific super-enhancer that interacts with the HOXA9 promoter via chromatin interactions.Significance Many oncogenes, such as MEIS1 and HOXA9, are overexpressed in some but not all cancers. We identified two key epigenetic mechanisms underlying this heterogeneity in oncogene expression in Acute Myeloid Leukemia. This mechanism could be potentially exploited to utilize epigenetic inhibitors to specifically target oncogene expression in cancer.Competing Interest StatementM.J.F declares two patents on methodologies related to ChIA-PET. No other conflicts of interest are declared.