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. 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. ***