A gene that is critical for normal mammary gland function during nursing helps trigger a highly lethal group of leukemias when it undergoes a mutation that fuses it to another gene, according to investigators at St. Jude Children's Research Hospital.
The discovery of the normal function of this gene suggests that drugs used to inhibit the activity of its mutated form might be used in leukemia patients with few serious side effects, the researchers said.
A report on this finding appears in the July 19 online posting of the August 6 issue of Molecular and Cellular Biology (MCB).
The researchers made their discovery while trying to determine the normal functions of a gene called MKL1 (megakaryoblastic leukemia 1), which is part of a mutation that causes acute megakaryoblastic leukemia (AMKL) in children, according to Stephan Morris, M.D., a member of Pathology and Oncology at St. Jude. AMKL is a leukemia in which megakaryocytes--the bone marrow cells that normally produce the blood platelets that control blood clotting--reproduce uncontrollably.
The leukemia mutation caused by the fusion of MKL1 to the gene RBM15 forms the RBM15-MKL1 fusion gene. AMKL resulting from this mutation usually has only a 20 to 25 percent survival rate.
"MKL1 is particularly interesting because it does not appear to be necessary for the normal development of blood cells," Morris said. "Yet when it's fused with RBM15, the resulting mutation causes AMKL. In addition, our finding that MKL1 plays a very limited role in the body suggests that if a drug were developed for leukemia treatment that prevents its abnormal function, such a drug might have only mild side effects." Morris is senior author of the MCB paper.
MKL1 belongs to a family of three proteins, each of which can bind to a protein called SRF, which in turn binds to genes that contain a DNA sequence (section of a gene) called the SRE, Morris said. SRF then activates a group of specific genes that cooperate to perform a particular function. The group of genes activated by SRF depends on which member of the MKL1 family binds to the SRF protein. This MKL1-linked SRF pathway is one of two such cellular signaling cascades of biochemical reactions that enable SRF to activate specific genes, according to Morris. The other pathway uses a group of three proteins collectively called TCF. These proteins help SRF bind to SRE DNA sequences and activate the expression of other genes.
"The MKL1 protein is normally active relatively widely throughout the body," Morris said. "So we were surprised that the loss of the MKL1 gene had such a limited effect. This probably reflects the fact that the other two protein members of the MKL1 family also can trigger the SRF pathway, as can TCF."
To study the role of MKL1, the team produced genetically modified mouse embryos that lacked the MKL1 gene (MKL1 -/- mice) and observed what happened in the mice when the gene was absent.
The investigators reported that about 40 percent of mouse embryos that lacked MKL1 did not survive to birth, although the mice that did survive appeared normal. However, the female mice that survived and grew to adulthood were not able to successfully nurse their offspring because they lacked MKL1 and were not able to expel milk from their mammary glands.
"The absence of the MKL1 gene impairs normal development and function of mammary gland muscle genes that depend on SRF," Morris said. "These muscles are the ones that contract and cause milk ejection in response to nursing."
The St. Jude team further demonstrated the normal role of MKL1 by using "gene chips" to analyze mammary tissues in MKL1 -/- mice. The researchers found that there was a significant reduction in activity of a group of genes linked to the development and differentiation (specialization of cells) of the myoepithelial muscle cells in the mammary gland. These muscles, which surround the tiny sacs in which milk accumulates, contract and squeeze the milk fluid into ducts throughout the mammary gland in response to nursing. The ducts, in turn, merge and empty their contents to nursing newborns.
In addition, the scientists found evidence that MKL1 may normally be required for maintaining milk production by the mammary glands during the period following birth. Specifically, the investigators showed that the expression (level of activity) of genes that are normally active only in mammary glands after weaning, when no milk is needed, is abnormally high in the absence of MKL1. In other words, when MKL1 was missing, these mammary gland genes behaved as if the mouse pups were no longer nursing and did not need milk.
The researchers also reported that the mouse embryos that did not survive had weak heart muscles that could not withstand stress in the uterus. This probably reflects the fact that some embryos in a large litter do not have a strong connection to the mother's placenta and therefore receive less blood and oxygen than their litter mates, Morris explained.
"The heart muscle of the normal mouse embryo can withstand the stress of mild oxygen and nutrient starvation," he said. "But in the absence of MKL1, the developing heart muscle simply gives out if stressed. That's probably why 40 percent of mouse embryos lacking the gene didn't survive.
"The discovery that MKL1 is a key player in activating specific genes linked to mammary gland function in otherwise healthy female mice is part of a larger story," he added. "It's a significant step that also gives us insight into the manner by which MKL1 mutations cause leukemia and represents progress on the long road to ultimately increasing the cure rate for AMKL."
Bonnie Kourvelas | EurekAlert!
Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg
Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | Universität Zürich
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
19.10.2017 | Materials Sciences
19.10.2017 | Materials Sciences
19.10.2017 | Physics and Astronomy