A combination of genetic mutations may explain the higher incidence of and poorer outcomes from pediatric leukemia in Hispanic and Latino patients, according to a new study published by Raca et al in the journal Leukemia. Researchers said a novel therapeutic drug combination—as well as testing for these mutations—may help address the disparity among patients with B-cell acute lymphoblastic leukemia (ALL).
Hispanic and Latino children are between 1.2 and 1.75 times more likely to develop B-cell ALL, the most common childhood cancer, than non-Hispanic and Latino children. They also have a 40% higher death rate than their counterparts after correcting for socioeconomic factors. A research team set out to understand the biology behind this health disparity after prior research suggested that there may be an increased frequency of a type of genetic mutation in Hispanic and Latino children with B-cell ALL.
Increased Incidence of Specific Mutations
The researchers studied 239 pediatric patients with B-cell ALL at Children’s Hospital Los Angeles and found two types of genetic mutations—a deletion of the IKZF1 gene, which holds instructions for cells to make the IKAROS protein; and a rearrangement, or translocation, of the gene with instructions for producing the CRLF2 protein—occurred more frequently in Hispanic and Latino children. IKZF1 deletion occurred two times more frequently in those children, making it the most frequent genetic alteration that signals poor prognosis of B-cell ALL. There was a fourfold increased incidence of CRLF2 translocations in Hispanic and Latino children as compared to non-Hispanic and Latino children.
“These mutations offer an explanation for the poor prognosis and increased incidence of [B-cell ALL] in Hispanic and Latino children and offer us insight into this pediatric cancer health disparity,” said study author Sinisa Dovat, MD, PhD, a researcher and pediatric oncologist at Penn State Children’s Hospital and Penn State Cancer Institute.
The researchers also found that 11% of Hispanic and Latino children had both mutations, compared with 0% of their counterparts. Almost all of the Hispanic and Latino children with B-cell ALL who had a specific type of CRLF2 translocation also had an IKZF1 deletion, while a large number of them had an IKZF1 deletion without that specific type of CRLF2 translocation. According to Dr. Dovat, these results suggest that IKZF1 deletion precedes or predisposes the CRLF2 gene to mutation.
Dr. Dovat said that further research is needed to understand the biologic mechanisms for why these genetic mutations happen more frequently in Hispanic and Latino children.
“Sequencing these genes in Hispanic and Latino children with [B-cell ALL] is essential to help pediatric oncologists determine a prognosis for these patients and develop appropriate treatment plans,” said Dr. Dovat. “Treatments that can restore the function of the IKAROS protein could be an efficient treatment for leukemia.”
Companion Study
In a companion study, also published in Leukemia by Ge et al, Dr. Dovat and colleagues outlined a treatment strategy that may be beneficial to patients. It involves targeting a protein, mTOR, that can lead to resistance to chemotherapy and poor prognosis when overproduced.
“The CRLF2 mutation, often found in Hispanic and Latino children with [B-cell ALL], leads to increased activity of mTOR, which has been associated with poor outcomes,” said Dr. Dovat. “We proposed that an effective treatment regimen would hinder the activity of the mTOR protein, but also target the gene that carries the instructions for making mTOR by restoring the function of the IKAROS protein.”
The researchers developed a combination therapy, starting with a drug that restores the function of IKAROS by inhibiting another protein called casein kinase 2 (CK2). When CK2 is prevented from carrying out its function, the IKAROS protein can keep mTOR from being produced. The team also used a second drug called rapamycin to inactivate mTOR proteins already present in cancer cells.
Dr. Dovat and his colleagues evaluated this approach in the lab by using the combination, and each drug individually, on cancer cells from Hispanic and Latino patients. They also later tested the approach against each drug individually and in combination in an animal model of leukemia using cancer cells from pediatric Hispanic and Latino patients with B-cell ALL. They found that in both instances, the combination of two drugs proved more effective against leukemia than either drug individually. These studies laid the groundwork for a phase I clinical trial with this treatment and provided a new paradigm for similar approaches to treat cancer using dual targeted treatments.
“We’ve identified a new approach for treating high-risk B-cell acute lymphoblastic leukemia,” said Dr. Dovat. “Our work established the foundation for clinical testing of a new combination therapy that may address health disparities and benefit patients who suffer from pediatric leukemia.”
Disclosure: For full disclosures of the study authors, visit nature.com/leu.
