Three-dimensional chromatin landscapes in MLLr AML [Micro-C]

Rearrangements of the mixed lineage leukemia (MLLr) gene are frequently associated with both pediatric and adult leukemia. However, the treatment options for these aggressive MLLr leukemias are limited due to the genomic complexity and dynamics of 3D structure in oncogene transcription and leukemia development. Here, we use Micro-C and transcriptome profiling to examine the MLLr-driven aberrant 3D genome architecture in gene-edited MLL-AF9 AML samples with biologically matched healthy donors. Recurrent and MLLr-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing in the same AML samples also revealed extensive and recurrent MLLr-specific promoter–enhancer and promoter–silencer loops. Overall, this study highlights the critical regulatory elements and provides rational and effective targeting strategy in MLLr AML. Micro-C for normal hematopoietic stem progenitor cells (HSPCs, CD34+, n=2) and acute myeloid cells (MLL-AF9 AML, n=2).