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

Manabu Kusakabe, Ann Chong Sun, Kateryna Tyshchenko, Rachel Wong, Aastha Nanda, Claire Shanna, Samuel Gusscott, Elizabeth A. Chavez, Alireza Lorzadeh, Alice Zhu, Ainsleigh Hill, Stacy Hung, Scott Brown, Artem Babaian, Xuehai Wang, Robert A. Holt, Christian Steidl, Aly Karsan, R. Keith Humphries, Connie J. Eaves, Martin Hirst and Andrew P. Weng ()
Additional contact information
Manabu Kusakabe: BC Cancer Agency
Ann Chong Sun: BC Cancer Agency
Kateryna Tyshchenko: BC Cancer Agency
Rachel Wong: BC Cancer Agency
Aastha Nanda: BC Cancer Agency
Claire Shanna: BC Cancer Agency
Samuel Gusscott: BC Cancer Agency
Elizabeth A. Chavez: BC Cancer Agency
Alireza Lorzadeh: University of British Columbia
Alice Zhu: University of British Columbia
Ainsleigh Hill: BC Cancer Agency
Stacy Hung: BC Cancer Agency
Scott Brown: BC Cancer Agency
Artem Babaian: BC Cancer Agency
Xuehai Wang: BC Cancer Agency
Robert A. Holt: BC Cancer Agency
Christian Steidl: BC Cancer Agency
Aly Karsan: BC Cancer Agency
R. Keith Humphries: BC Cancer Agency
Connie J. Eaves: BC Cancer Agency
Martin Hirst: University of British Columbia
Andrew P. Weng: BC Cancer Agency

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-10510-8

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