DALLAS – April 8, 2021 – New research has revealed the surprising role of so-called jumping genes, which are the source of genetic mutations responsible for many human diseases. In a new study by the Children’s Medical Center Research Institute at UT Southwestern (CRI), scientists made the unexpected discovery that these DNA sequences, also known as transposons, can protect against certain blood cancers.
These findings are published in Nature Genetics, led scientists to identify a new biomarker that could help predict how patients will respond to cancer therapies and find new therapeutic targets for acute myeloid leukemia (AML), the deadliest type of blood cancer in adults and children.
Transposons are DNA sequences that can be activated or moved from one place in the genome to another. Although there are many different classes of transposons, scientists at Laboratory Xu have focused on a type known as the long-stained element-1 (L1) retrotransposon. L1 sequences work by copying and then gluing to different locations in the genome, often leading to mutations that can cause diseases like cancer. Almost half of all cancers contain mutations caused by the insertion of L1 into other genes, especially cancers of the lung, colon and colon, and head and neck. The incidence of L1 mutations in blood cancers such as AML is extremely low, but the reasons for which are poorly understood.
When researchers examined human AML cells to identify genes necessary for cancer cell survival, they found that MPL8, a known regulator of L1, selectively requires AML cells. Curious to understand the basic basis of this connection, scientists at Laboratory Xu studied how L1 sequences are regulated in human and mouse leukemia cells. They discovered two key discoveries. The first was that MPP8 blocked the copying of L1 sequences in AML-initiating cells. The second was that when L1 activity is involved, it can compromise the growth or survival of AML cells.
“Our initial finding was a surprise because it has long been thought that activated transposons promote cancer development by generating genetic mutations. We found that the opposite is true for blood cancers, and that reduced L1 activity is associated with poorer clinical outcomes and resistance to therapy,” he says. dr. Jian Xu, associate professor at CRI and senior author of the study.
MPP8 thus suppressed L1 to protect the cancer cell genome and allow AML-initiating cells to survive and proliferate. Cancer cells, just like healthy cells, need to maintain a stable genome in order to replicate. Too many mutations, such as those created by L1 activity, can impair the replication of cancer cells. The researchers found that L1 activation led to genome instability, which in turn activated a DNA damage reaction that triggered cell death or eliminated the cell’s ability to replicate. Xu believes this finding may provide a mechanical explanation for the unusual sensitivity of myeloid leukemia cells to therapies that cause DNA damage and are currently used to treat patients.
“Our discovery that L1 activation can suppress the survival of certain blood cancers opens up the possibility of its use as a prognostic biomarker and the possible exploitation of its activity to target cancer cells without affecting normal cells,” Xu says.
Xu is an associate professor of pediatrics at UT Southwestern and the Texas Institute for Cancer Prevention and Research (CPRIT), a cancer research scientist. Leading authors from Xu Laboratories include Zhimin Gu and Yuxuan Liu. Other collaborators include John Abrams and Alec Zhang of UT Southwestern and Wenfeng An of South Dakota State University.
This work was supported by the National Institutes of Health (R01CA230631 and R01DK111430), CPRIT (RR140025, RP180504, RP180826 and RP190417), the Leukemia and Lymphoma Scholarship Award, the American Hematology Association Award, the Welukemia Foundation Research Foundation Award -1942) and donors of the Children’s Medical Center Foundation.
The Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center of Dallas, a leading children’s health hospital. The mission of CRI is to conduct transformative biomedical research to better understand the biological basis of the disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians researching the interface of regenerative medicine, cancer biology, and metabolism. For more information, visit: cri.utsw.edu. To support CRI, visit: give.childrens.com/about-us/why-help/cri/.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s leading academic medical centers, integrates pioneering biomedical research with outstanding clinical care and education. The faculty has received six Nobel Prizes and includes 23 members of the National Academy of Sciences, 17 members of the National Medical Academy and 13 researchers from the Howard Hughes Medical Institute. The full-time faculty with more than 2,800 is responsible for revolutionary medical advances and is committed to the rapid translation of science-based research into new clinical treatments. UT Southwestern physicians provide care in about 80 specialties for more than 105,000 hospitalized patients, nearly 370,000 emergency cases, and monitor approximately 3 million outpatient visits annually.
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