UT Southwestern Discovers BRCA1 Gene is Vital for Forming Blood Cells

Researchers with the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center recently discovered the BRCA1 gene is necessary for the survival of blood-forming stem cells. This could explain why patients with BRCA1 mutations do not have an elevated risk for leukemia, since the stem cells die before they have an opportunity to transform into a blood cancer.

BRCA1 is a human gene producing tumor-suppressor proteins to help repair damaged DNA, according to the National Cancer Institute. If BRCA1 is altered, DNA damage may not repair properly. If a BRCA gene mutation occurs, this can increase the risk for breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.

Dr. Theodora Ross, professor of internal medicine and director of the cancer genetics program at UT Southwestern, says their data suggests a “die or transform hypothesis” regarding inherited mutations in BRCA1. This could explain why the mutations cause cancer in specific tissues, such as breast and ovaries, rather than in all tissues.

According to Ross, complementary findings from two separate experiments, both initiated in 2010, resulted in the BRCA1 discovery.

“We were conducting research on the BCR/ABL oncogene and found that when we made the BCR/ABL human mutation in mice, it did not give us the leukemia we expected,” Ross said in an interview. “We found that we needed to add additional mutations. During these experiments we tried adding a Brca1 mutation. Instead of yielding leukemia, the mice experienced bone-marrow failure.”

Ross and other researchers found that crossing their BRCA1 mutant mice with the BCR/ABL mutant mice also did not result in leukemia, as predicted, but in bone-marrow failure, ultimately attributed to the BRCA1 alone.

Ross says these findings coincided with their parallel work to construct a mouse model where the mouse BRCA1 gene was replaced with the human BRCA1 gene. They started to construct this new model in 2010 and recently completed the first set of experiments with this model that investigated human BRCA1 mutations in mouse blood stem cells.

“It was a serendipitous discovery,” Ross said. “When we followed up with it, we found if you don’t have a normal BRCA1 on either of your two chromosomes, you don’t form a blood stem cell, and that may be why you’re not at risk for leukemia. The cells with two dead BRCA1 genes die. So, if you do have a mutation on one of your chromosomes, you don’t get leukemia at a rate that is higher than the normal population.”

The recent discovery by UT Southwestern shows how complex the BRCA1 continues to be. It was discovered in 1994 and is still intently researched by laboratories across the U.S.

“This discovery just shows how long it takes to go from the fundamentals of basic science to finding things that might have human relevance,” Ross said. “There’s still so much to uncover.”

Posted in News, Research.