AbstractAcute Myeloid Leukemia (AML) is a highly lethal blood cancer arising due to aberrant differentiation of haematopoietic stem cells. Here we obtained 3D genome organization maps by Hi-C in the CD34+ haematopoietic stem cells from three healthy individuals and eight individuals with AML, and found that AML have increased loops to oncogenes compared with normal CD34+ cells. TheMEIS1oncogenic transcription factor is regulated by a Frequently Interacting Region (FIRE). This FIRE is only present in normal bone marrow samples, and four of eight AML sample. FIRE presence is associated withMEIS1expression. CRISPR excision of a FIRE boundary led to loss ofMEIS1and reduced cell growth. Moreover, MEIS1 can bind to the promoter ofHOXA9, and HOXA9 shows gain of Acute Myeloid Leukemia-specific super-enhancers that loop to theHOXA9promoter.SignificanceWe found that Acute Myeloid Leukemias have more chromatin loops to oncogenes compared with normal blood stem cells. We identified heterogeneity in chromatin interactions at oncogenes, and heterogeneity in super-enhancers that loop to oncogenes, as two key epigenetic mechanisms that underlieMEIS1andHOXA9oncogene expression respectively.