and Ross Dickins, PhD
Credit: Walter and Eliza Hall
Institute of Medical Research
Results of preclinical research suggest B-progenitor acute lymphoblastic leukemia (B-ALL) can be “reversed” by coaxing leukemic cells back into normal development.
Researchers found that switching off the gene Pax5 could induce B-ALL in mice, but restoring Pax5 function could prompt disease remission.
Grace Liu, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and her colleagues detailed this research in Genes & Development.
“Pax5 is essential for normal development of [B cells],” Liu said. “When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous.”
The researchers used transgenic RNAi to suppress endogenous Pax5 expression in the hematopoietic compartment of mice, and this induced B-ALL.
“Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukemia cells, which has been shown before,” Liu said. “However, we showed, for the first time, that reactivating Pax5 enabled the cells to resume their normal development and lose their cancer-like qualities, effectively curing the leukemia.”
The team found that restoring endogenous Pax5 expression triggered immunophenotypic maturation and durable disease remission.
Even brief Pax5 restoration disabled B-ALL cells’ leukemia-initiating capacity in mice. And the researchers observed similar results in human B-ALL cell lines.
“This work shows how inactivating the tumor suppressor gene Pax5 contributes to B-ALL development and how leukemia cells become addicted to low Pax5 levels to continue proliferating,” said study author Ross Dickins, PhD, also of the Walter and Eliza Hall Institute of Medical Research.
“Even though the B-ALL cells have multiple genetic mutations, simply reactivating Pax5 causes tumor cells to resume normal development and lose their cancerous properties.”
Dr Dickins added that forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukemia. However, genes lost in tumor cells are not traditionally considered suitable drug targets.
“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” Dr Dickins said. “However, by understanding the mechanisms by which Pax5 loss causes leukemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function.”
