Research shows that two genetic mutations could be behind the higher incidence and worse prognosis of B-cell acute lymphoblastic leukemia in children from Hispanic or Latino backgrounds.
The team behind the study, a collaboration between Pennsylvania State University, the University of Southern California and California-based Loma Linda University, hopes a therapeutic strategy targeting these two variants could help improve prognosis for children in this group.
Hispanic or Latino (HL) children are between 1.2 and 1.75 times more likely to develop B-cell acute lymphoblastic leukemia (B-ALL) than non-HL children. They also have a worse prognosis when diagnosed and are 40% more likely to die from the cancer compared with other children, after correcting for socio-economic factors.
Previous studies have shown some genetic differences in this group, which might explain the higher rates, but reasons for the significantly worse prognosis in these children were unclear.
To try and investigate the genetics behind these differences further, a collaborative study was set up. Overall, 239 children with B-ALL were recruited at the Children’s Hospital of Los Angeles — 164 HL and 75 non-HL. The researchers found two mutations that occurred more frequently in HL vs non-HL children. A deletion in the IKZF1 gene, encoding the DNA binding protein IKAROS, and a rearrangement where the immunoglobulin heavy chain locus gene (IGH) is translocated to the CRLF2 gene, which is involved in blood cell development.
The IKZF1 deletion occurred in 29% of HL children versus 15% of non-HL children. The IGH-CRLF2 translocation was also more common in HL compared with non-HL patients at 12% vs 2.7%, respectively. Notably, 11% of HL children had both mutations, which was not seen in any of the other group.
“These mutations offer an explanation for the poor prognosis and increased incidence of B-ALL in Hispanic and Latino children and offer us insight into this pediatric cancer health disparity,” said Sinisa Dovat, a researcher and pediatric oncologist at Penn State. Dovat co-led the study, which was published in the journal Leukemia.
There seems to be a sequential link between the two mutations. Almost all the HL children with the IGH-CRLF2 translocation also had the IKZF1 deletion, but many had the IKZF1 deletion but not the IGH-CRLF2 translocation. Dovat believes this may mean the IKZF1 deletion comes first and could even predispose the children who have it to the IGH-CRLF2 translocation.
“Sequencing these genes in Hispanic and Latino children with B-ALL is essential to help pediatric oncologists determine a prognosis for these patients and develop appropriate treatment plans,” Dovat said. “Treatments that can restore the function of the IKAROS protein could be an efficient treatment for leukemia.”
Dovat and his colleagues have already started designing some potential therapies for these children, as described in another article also published in the journal Leukemia.
The researchers believe that part of the reason children with the IGH-CRLF2 translocation have poor outcomes is due to it triggering higher levels of a protein called mTOR. This protein has previously been linked to chemotherapy resistance and a generally poor prognosis.
The therapeutic strategy, which was tested on cell lines in the lab and in a mouse model, involves a new candidate drug to restore the function of the IKAROS protein, which helps keep levels of mTOR low. To further suppress mTOR proteins that are already present in the cancer cells, the team added the drug rapamycin to the trial therapy.
Dovat and colleagues now plan to trial this combination in a phase I study. “We’ve identified a new approach for treating high-risk B-cell acute lymphoblastic leukemia,” he commented. “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.”
