Study illuminates genetic understanding of aggressive childhood leukemias

New research published today in JAMA Oncology reports how two separate DNA changes appear to predict aggressive childhood leukemia when they occur in combination.

Over the course of a decade of work at various research sites across multiple continents, the researchers evaluated tumor characteristics of more than 1,300 childhood cancer patients diagnosed with B-cell acute lymphoblastic leukemia (ALL), a type of cancer that affects the white blood cells of the bone marrow.

ALL is the most common cancer in children, according to the Leukemia & Lymphoma Society. This study highlights the genetic understanding of this disease in children with the worst outcomes, including relapse and/or death.

The research team examined the DNA of leukemia cells to look for generalized changes.

We found that a barely detectable region of DNA, known as 22q11.22, was missing in approximately 30-40% of pediatric B-cell ALL patients.”

Joshua Schiffman, MD, study co-senior author, Huntsman Cancer Institute at the University of Utah

Schiffman is a pediatric cancer physician scientist at the Huntsman Cancer Institute (HCI) and a professor of pediatrics at the University of Utah (U of U). “We started to wonder if something so small was missing so often, could this missing piece of DNA affect survival?” Then the research team turned their attention to a much better known gene for childhood leukemia called IKZF1.

“The changes in IKZF1 have puzzled doctors for a while,” explains Luke Maese, DO, a pediatric oncologist at HCI and an associate professor of pediatrics at the U of U, who cares for children with leukemia at Intermountain Primary Children’s Hospital. “We’ve known for over a decade that IKZF1 changes predict very poor outcome in some, but not all, patients.” The research team set out to investigate whether this missing portion of 22q11.22 could interact with IKZF1 changes to more reliably predict the results.

“Certainly, we found that patients with both the 22q11.22 deletion and the IKZF1 changes — collectively known as a ‘double deletion’ — had some of the worst outcomes in childhood leukemia,” says Schiffman. The team found that patients who already had an IKZF1 change were almost twice as likely to relapse if they also had a deletion in the 22q11.22 region.

The research team used advanced genomic analysis techniques to evaluate both heritable and environmental changes in the tumors of children with B-cell ALL. They evaluated genomic information from childhood cancer patients in multiple states and countries. The study included cohorts of leukemia patients in children with Down syndrome. Children with Down syndrome have a higher risk of leukemia.

David Spencer Mangum, MD, co-lead author and now an assistant professor of pediatric hematology/oncology at Nemours Children’s Health, recalls starting work on this study more than 10 years ago as a medical student working in Schiffman’s lab at HCI. visited.

“During all my training years, we have always been trying to understand how this 22q11.22 deletion might affect children with leukemia. We collected data from many different clinical studies to ensure that this finding was real and reproducible,” explains Mangum. “Our findings are significant because we found that the odds of relapse and death were consistent across multiple different cohorts of children with ALL, including children with Down syndrome.”

The research team hopes this finding could provide new insights into treatments for childhood leukemia. For example, the frequency of the 22q11.22 focal deletion indicates that it may be important for the development of leukemia, and its combined association with worse outcomes means it could be a useful clinical prognostic marker in the future. “Children with double deletions may need more treatment – ​​or bone marrow transplants right away – while children without double deletions may need less toxic chemotherapy to still achieve excellent results. All of this needs further investigation,” says Schiffman

Source:

Huntsman Cancer Institute at the University of Utah

Reference magazine:

Mangum, DS, et al. (2021) Association of combined focal 22q11.22 deletion and IKZF1 changes with outcomes in childhood acute lymphoblastic leukemia. JAMA Oncology. doi.org/10.1001/jamaoncol.2021.2723.

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