Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia. Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia

We report here an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yields aggressive leukemia that appears indistinguishable from natural disease. We utilize this synthetic model to uncover a role for oncogene-induced HOXB activation which is operative in leukemia cells-of-origin and persists in established tumors where it defines a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. We show further that anterior HOXB genes are specifically activated in human T-ALL by an epigenetic mechanism and confer growth advantage in both pre-leukemia cells and established clones. Overall design: We performed epigenetic profiling (H3K27me3, H3K27ac) using massively parallel sequencing-based assays on CD34+ human cord blood cells transduced with a combination of activated NOTCH1 (NOTCH1ΔE, encoded on a GFP-tagged lentiviral vector) and LMO2/TAL1/BMI1 (encoded on an mCherry-tagged lentiviral vector), and then cultured on OP9-DL1 feeders. Non-transduced cells sorted from the same cultures as transduced cells serve as negative controls. *** Raw data provided at European Genome-phenome Archive (EGA) under accession EGAS00001003627. ***