Using a genetic switch system, a team of researchers has successfully reversed a type of leukemia in a mouse model of the disease. They found that switching back on a particular gene known to facilitate tumor development triggered the cancerous cells to resume normal development, leading to disease remission. The study has been published in Genes & Development.
Leukemia is a group of cancers of blood cells that usually begin in the bone marrow. B-progenitor acute lymphoblastic leukemia (B-ALL) is the most common childhood leukemia which is characterized by an accumulation of undifferentiated cells called lymphoblasts. These cells usually differentiate (mature) into white blood cells called lymphocytes, but in B-ALL they get stuck in this immature state, replicating uncontrollably and consequently forming tumors that interfere with normal blood cell production.
It is known that a mutation in a gene called Pax5 is critical to the development of B-ALL in both mice and humans; however, little was known about how precisely the loss of this gene contributes to the initiation and progression of this disease.
Pax5 is a type of tumor suppressor gene which is a gene that acts to negatively regulate cell replication and thus inhibit tumor development. It is well understood that these genes are lost or inactivated in a variety of cancers and consequently a lot of research has focused on finding ways to overcome this.
In order to investigate the role of Pax5 in B-ALL, researchers headed by Dr Ross Dickins from the Walter and Eliza Hall Institute adopted a genetic switch system called RNA interference to reversibly suppress Pax5 expression in the bone marrow of mice. When the gene was switched off the mice developed B-ALL; however, when they switched the gene back on the mice went into remission and the tumor cells shed their cancerous properties.
“Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukemia cells, which has been shown before,” said lead author Grace Liu in a news-release. “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. What was intriguing for us was that simply restoring Pax5 was enough to normalize these cancer cells, despite the other genetic changes.”
According to Dickins, this research has helped further our knowledge of the role of Pax5 in tumor development. “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,” he said.
Dickins also mentioned that while B-ALL patients have a relatively good prognosis, current treatments are far from perfect given the side-effects. Forcing B-ALL cells to enter normal development may therefore represent a promising treatment avenue, but targeting genes involved in tumor development is tricky business.
“It is very difficult to develop drugs that restore the function of genes that are lost during cancer development,” said Dickins. “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.”