Quebec-based researchers partly funded by the TFRI have uncovered the key mutation that leads to the development of giant cell tumour of the bone (GCT), a locally aggressive bone tumour that affects adults ages 20-40.
In a paper published in Cancer Discovery (October 2020), the team led by Drs. Nada Jabado, a pediatric hemato-oncologist at the Goodman Cancer Center, and Claudia Kleinman, an Assistant Professor of Human Genetics at McGill University, revealed that a single mutation in a gene called Histone 3.3 is responsible for the development of this type of tumour.
According to the team, mutations in Histone 3.3 impede a type of cell known as an “ancestor cell” from specializing into other cells, pushing it instead to start making identical copies of itself that form into a tumour. This tumour eventually destroys the surrounding healthy bone and in rare occasions has been known to metastasize to other parts of the body.
“We discovered that this mutation in Histone 3.3 turns off a series of genes needed for bone cells to acquire their specialized function,” explained Terry Fox New Investigator Dr. Livia Garzia, a biologist and pediatric cancer researcher at the Cancer Research Program of the Research Institute of the McGill University Health Centre, who participated in the study. “By doing this, this single mutation can influence the state of ancestor cells and reprogram their function.”
Perhaps more importantly, the team found that when they genetically engineered cells with this mutation in the lab, the tumour stopped growing and the cells reacquired some of their more specialized functions. While there is no way to currently do this in patients, the discovery opens the door for further research into ways to fix this key mutation.
“What we found is that in the lab, once this system is corrected, the engineered cells never reverted back to form tumours,” said Dr. Garzia. “This means that if we can find a way to correct the mutation in people or push the tumour cells toward a more specialized state with a drug, GCT could be cured.”
H3.3G34W promotes growth and impedes differentiation of osteoblast-like mesenchymal progenitors in Giant Cell Tumour of Bone
Sima Khazaei, Nicolas De Jay, Shriya Deshmukh, Liam D. Hendrikse, Wajih Jawhar , Carol C.L. Chen , Leonie G. Mikael , Damien Faury , Dylan M. Marchione , Joel Lanoix , Éric Bonneil, Takeaki Ishii , Siddhant U. Jain , Kateryna Rossokhata , Tianna S. Sihota, Robert Eveleigh , Véronique Lisi , Ashot S. Harutyunyan , Sungmi Jung , Jason Karamchandani , Brendan C. Dickson , Robert Turcotte , Jay S. Wunder , Pierre Thibault , Peter W. Lewis, Benjamin A. Garcia , Stephen C. Mack, Michael D. Taylor , Livia Garzia , Claudia L. Kleinman, Nada Jabado
This study is partly funded by a Terry Fox New Investigator Award in Deciphering metastasis maintenance events in adolescents and young adults' sarcoma
to Dr. Livia Garzia