Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia.
Manabu KusakabeAnn Chong SunKateryna TyshchenkoRachel WongAastha NandaClaire ShannaSamuel GusscottElizabeth A ChavezAlireza LorzadehAlice ZhuAinsleigh HillStacy HungScott BrownArtem BabaianXuehai WangRobert A HoltChristian SteidlAly KarsanR Keith HumphriesConnie J EavesMartin HirstAndrew P WengPublished in: Nature communications (2019)
Mechanistic studies in human cancer have relied heavily on cell lines and mouse models, but are limited by in vitro adaptation and species context issues, respectively. More recent efforts have utilized patient-derived xenografts; however, these are hampered by variable genetic background, inability to study early events, and practical issues with availability/reproducibility. 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.
Keyphrases
- endothelial cells
- acute myeloid leukemia
- bone marrow
- cord blood
- induced pluripotent stem cells
- genome wide
- pluripotent stem cells
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- gene expression
- dna methylation
- squamous cell carcinoma
- mouse model
- ejection fraction
- peritoneal dialysis
- cell cycle arrest
- signaling pathway
- endoplasmic reticulum stress