A strong inherited genetic basis of acute lymphocytic leukemia (ALL) risk in children has been identified.

‘Inherited genetic mutations in the gene IKZF1 confer a higher likelihood of developing pediatric acute lymphocytic leukemia.’

The
findings are among the latest evidence to point to a strong inherited
genetic basis of ALL risk in children. Some of the variants identified
also appear to reduce cancer cells' sensitivity to a chemotherapy drug
used to treat some types of ALL, potentially contributing to drug
resistance. 




"The genetic variants help explain why these children develop leukemia and also inform potential risk for ALL in family members who carry the same defective version of IKZF1," said lead study author Michelle L. Churchman of St. Jude Children's Research Hospital in Memphis. "If patients are identified as having one of these deleterious IKZF1 mutations, then that could potentially inform their treatment, whether family members need to get screened, or other clinical decisions."
The new study was initiated after multiple cases of pediatric ALL were reported in a single family in Germany and a genetic analysis of the family members pointed to an inherited mutation in IKZF1 as a possible contributor. The IKZF1 gene encodes Ikaros, a protein with essential roles in lymphocyte development. Previous studies have found defects in IKZF1 in leukemia cells linked with some high-risk forms of ALL that respond poorly to treatment, such as BCR-ABL1 (Philadelphia chromosome) ALL.
The researchers sequenced the IKZF1 gene in germline DNA from normal blood samples of more than 5,000 children with ALL treated by St. Jude Children's Research Hospital and other collaborating institutions in the Children's Oncology Group and identified 28 gene variants. They then introduced these variant forms of IKZF1 into cultured cells to gauge their effects on activity of the Ikaros protein, cell growth and behavior, and response to chemotherapeutic agents.
The results showed that most of the gene variants caused abnormalities conducive to the development of leukemia, such as increased cellular aggregation and "stickiness" of cells in the bone marrow. Several variants significantly reduced the sensitivity of leukemic cells to the chemotherapy drug dasatinib, a drug commonly used to treat high-risk forms of ALL such as BCR-ABL1.
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The team plans to continue to study the clinical outcomes of patients with IKZF1 variants, further assess the degree to which these mutations increase the risk of ALL in families, and integrate different types of genomic studies for a more complete picture of how these mutations are inherited.
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