Cell of Origin in AML: Susceptibility to MN1-Induced Transformation Is Regulated by the MEIS1/AbdB-like HOX Protein Complex

SummaryPathways defining susceptibility of normal cells to oncogenic transformation may be valuable therapeutic targets. We characterized the cell of origin and its critical pathways in MN1-induced leukemias. Common myeloid (CMP) but not granulocyte-macrophage progenitors (GMP) could be transformed by MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that MN1-leukemogenicity required the MEIS1/AbdB-like HOX-protein complex. ChIP-sequencing identified common target genes of MN1 and MEIS1 and demonstrated identical binding sites for a large proportion of their chromatin targets. Transcriptional repression of MEIS1 targets in established MN1 leukemias demonstrated antileukemic activity. As MN1 relies on but cannot activate expression of MEIS1/AbdB-like HOX proteins, transcriptional activity of these genes determines cellular susceptibility to MN1-induced transformation and may represent a promising therapeutic target.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (5387 K)

► CMPs but not GMPs are the cells of origin in MN1 leukemias
► MEIS1/AbdB-like HOX proteins determine susceptibility to MN1 transformation
► MN1 and MEIS1 colocalize at promoters of 537 differentially expressed genes
► Transcriptional repression of MEIS1 target genes inhibits MN1 leukemias