Can Flipping a Genetic Switch Help Treat a Common Childhood Leukemia?

Acute lymphoblastic leukemia (ALL) accounts for one-fourth of all cancers among children up to age 15, with 3000 children diagnosed each year and rising.

While survival rates are improving—thanks to better chemotherapy, bone marrow transplants, and now immunotherapy—treatments still take a toll physically and financially. And they don’t work for everyone.

So, researcher Matthew R. Hart, PhD, working in the lab of Marshall S. Horwitz, MD, PhD, at the University of Washington’s Institute for Stem Cell and Regenerative Medicine, set out to explore a new way to treat ALL based on what is known about the genetics of the disease.

ALL starts when bone marrow makes too many white blood cells, the “lymphocytes” that are referenced in the name. When these cells rapidly multiply and crowd out healthy immune cells, the body cannot fight infections.

The Horwitz lab focused on the PAX5 gene, since mutations of this gene are seen in about one-third of the patients who develop ALL. “Others have previously shown that restoring PAX5 can correct [B-cell] growth, but how to do that in ALL patients is now obvious,” Horwitz said in a statement. “We do know that PAX5 is related to 2 other gene family members, PAX2 and PAX8, which are not mutated in leukemia. What we were able to show is that you can turn on PAX2 to functionally replace PAX5."

In other words, by finding a way to chemically flip a switch to get a related gene to take over, a new treatment method could be created.

In the case of ALL, just as it has been shown that restoring PAX5 expression repairs B-cell function and leads to disease remission, if PAX2 can be activated as a substitute for PAX5 by triggering it in the kidneys or other tissues, it can “substitute for PAX5 and restore differentiation in ALL cells,” according to the authors.

Already, it is known that PAX2 expression is activated by changes in salt levels, and PAX5 expression is restored when leukemia cells are similarly treated. So, treatments could be designed to target his mechanism.

The authors, reporting in PLOS Genetics, said their work has potential to yield treatments in many other diseases, including other cancers.

Reference

Hart MR, Anderson DJ, Porter CC, et al. Activating PAX gene family paralogs to complement PAX 5 leukemia driver mutations [published September 14, 2018]. PLOS Genetics. https://doi.org/10.1371/journal.pgen.1007642.