For the first time ever, a team of TFRI-funded researchers has created synthetic cancer cells that are indistinguishable from T-cell acute lymphoblastic leukemias (T-ALL) found in patients, setting the stage to make important laboratory discoveries on the ways these cancers grow and spread.
In a paper published in Nature Communications (July 2019), the team explains how this important creation can help the study of human leukemias.
“Despite the many and important conceptual insights that mouse models have brought to our understanding of human cancer, they are, by definition, incapable of revealing mechanisms that are dependent on human-specific elements,” explains Dr. Andrew Weng, a clinician-scientist at BC Cancer, and the paper’s senior author. “Our approach here in modeling human cancer using human cells, though simple in concept, represents in our opinion the next logical step towards improving the way we study cancer.”
In fact, these synthetic cancer cells have already allowed the team to make an important discovery: understanding the role that a family of genes known as HOXB plays in the initiation and maintenance of human leukemias.
“Our synthetic model allowed us to uncover that HOXB is operative in leukemia cells-of-origin and persists in established tumours where it defines a novel subset of patients distinct from other known genetic subtypes,” says Dr. Weng. Further, patients with high levels of HOXB activation were also discovered to have poor clinical outcome.
Having been able to make this discovery, the team is excited for the impact that their new synthetic cancer cells will have on the creation of possible treatments for T-ALL, a subtype of acute lymphoblastic leukemias (ALL) with five-year survival rate of 40 per cent in adults. Pediatric patients do much better with five-year survival rates of over 90 per cent; however, this is after 2-3 years of intensive chemotherapy and thus less toxic treatments are needed.
“Besides its utility as a tool for discovery of basic mechanisms of human cell transformation and leukemogenesis, synthetic modeling offers a genetically defined, yet highly customizable platform that may also prove useful for targeted drug screening/validation efforts and functional testing of patient-specific genetic variants,” says Dr. Weng.
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 & Andrew P. Weng
This study was partially funded by a Terry Fox New Frontiers Program Project Grant in Exploiting Pathogenic Mechanisms in Acute Leukemia for Clinical Translation