Individuals with ALL make too many lymphoblasts, leaving little room for mature, healthy white blood cells, red blood cells, and platelets. As a result, people with ALL are prone to developing anemia and infections.
While children under the age of 5 years old have the greatest risk of ALL, the vast majority of deaths from the disease occur in adults.
In 2017, there are expected to be approximately 5,970 new cases of ALL diagnosed in children and adults in the U.S., and around 1,440 deaths from the disease.
When it comes to treating ALL, chemotherapy is often the first port of call. Other treatments, such as stem cell transplantation, radiation therapy, surgery, and targeted drugs, may also be an option.
Identifying a safer treatment for ALL
According to study co-author Gisele Monteiro, of the School of Pharmaceutical Sciences at the University of São Paulo in Brazil, an enzyme isolated from the bacteria Escherichia coli and Erwinia chrysanthemi (called L-asparaginase) has been used in the treatment of ALL for decades.
While treatment with this bacterial enzyme can lead to high remission rates, Monteiro notes that it can trigger mild to severe immune responses in around 25 percent of patients. As such, a less toxic biopharmaceutical for the treatment of ALL is required.
In a study published in the journal Scientific Reports, Monteiro and team reveal how they isolated an L-asparaginase-like enzyme from the non-bacterial source Saccharomyces cerevisiae, more commonly known as baker's yeast or brewer's yeast.
"Our goal in this project wasn't to produce the enzyme, but rather to find a new source of the biodrug in microorganisms for use in patients who develop resistance to the bacterial enzyme," says study co-author Marcos Antonio de Oliveira, of the Biosciences Institute at São Paulo State University in Brazil.
Isolating an L-asparaginase-like enzyme from yeast
To reach their findings, the researchers used bioinformatics tools in order to analyze the genomes of several fungi known to secrete asparaginase.
From this, the team identified a gene in S. cerevisiae called ASP1 that encodes an enzyme similar to L-asparaginase.
First study author Iris Munhoz Costa, also of the School of Pharmaceutical Sciences at the University of São Paulo, explains that unlike bacteria, yeast is eukaryotic. This means that it contains a membrane-covered nucleus consisting of genetic material, as is the case with human cells.
As such, it is hypothesized that yeast-derived enzymes are less likely than bacterial enzymes to trigger severe immune responses.
With this in mind, the researchers cloned the ASP1 gene, and with the help of genetic engineering, they were able to prompt E. coli to produce a purified form of yeast-derived L-asparaginase.
"We were able to obtain the recombinant protein," notes Costa. "We then performed studies to characterize its secondary structure and identify important regions called catalytic sites. Finally, we evaluated its efficacy in vitro."
Purified, yeast-derived L-asparaginase less toxic for healthy cells
The researchers tested both the purified L-asparaginase from yeast and L-asparaginase from E. coli on three groups of human leukemia cells. One group of cells was unable to produce normal amounts of asparagine (MOLT4), one group produced asparagine at normal levels (REH), and the last group (the control group) was non-malignant (HUVECs).
The team found that the purified, yeast-derived L-asparaginase killed approximately 70-80 percent of MOLT4 cells, compared with 90 percent for E. coli-derived L-asparaginase. However, purified L-asparaginase from yeast was found to be less toxic to HUVECs than L-asparaginase from E. coli.
Neither form of L-asparaginase was found to be effective against REH cells, the team reports.
Overall, the researchers say that their findings indicate that yeast-derived L-asparaginase may be a safer, more effective treatment for ALL.
"In this study we characterize the enzyme L-asparaginase from S. cerevisiae. The results show this protein can efficiently annihilate leukemia cells with low cytotoxicity to healthy cells."
The team now plans to conduct in vitro studies of L-asparaginase from yeast in order to gain a better understanding of its toxicity in various types of cells, as well as the immune response to the enzyme.
If such studies show promise, the researchers would then like to see how yeast-derived L-asparaginase performs in animal models of ALL.
Recombinant L-asparaginase 1 from Saccharomyces cerevisiae: An allosteric enzyme with antineoplastic activity, Gisele Monteiro et al., Scientific Reports, doi:10.1038/srep36239, published online 8 November 2015.
Fundação de Amparo à Pesquisa do Estado de São Paulo news release, accessed 18 January 2017 via EurekAlert.
Additional source: American Cancer Society, What are the key statistics about acute lymphocytic leukemia?, accessed 18 January 2017.