Small Change

Inherited DNA Alteration Explains Overactive Leukemia Gene

Albert de la Chapelle 2A new study shows that a small inherited change in DNA is largely responsible for overactivating a gene linked to poor treatment response in people with acute leukemia.

The study, led by researchers at the OSUCCC – James, focused on the BAALC gene, which is often overexpressed in acute myeloid or acute lymphoblastic leukemia. This work indicates that these diseases will likely respond poorly to standard therapy.

Researchers discovered that BAALC overexpression is caused by a small change called a single nucleotide polymorphism (SNP) in the gene’s DNA. The SNP alters the gene’s “on” switch, allowing a different molecule to keep it “running” when it shouldn’t.

“This SNP doesn’t raise risk of developing leukemia, but it predisposes to overexpression of the BAALC gene, which is associated with leukemia development and poor response to treatment,” says principal investigator Albert de la Chapelle, MD, PhD, co-leader of the Molecular Biology and Cancer Genetics Program at the OSUCCC – James.

The findings suggest this SNP could be a useful prognosis marker and help guide therapy in acute leukemia patients.

Researchers say the DNA change caused by the SNP creates a binding site for an activating molecule called RUNX1, which is also involved in forming normal and malignant blood cells. The scientists showed that patients with high levels of RUNX1 protein also had high BAALC expression, while those with low RUNX1 protein had low BAALC gene expression.

For this study, de la Chapelle and colleagues used DNA sequencing to examine the genomic region of BAALC in 253 patients with cytogentically normal AML treated in Cancer and Leukemia Group B clinical trials. The analysis revealed nine SNPs of interest, but the researchers focused only on one called rs62527607[T].

“We doubt that this SNP is entirely responsible for BAALC overexpression, but we believe it is a major contributor,” de la Chapelle says.

Published in Proceedings of the National Academy of Sciences.

Supported in part by NIH/National Cancer Institute grants CA098933, CA101140, CA114725, CA140158, CA31946, CA33601, CA16058, CA77658 and CA129657.

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