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!
First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife
Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
26.10.2016 | Power and Electrical Engineering
26.10.2016 | Awards Funding
26.10.2016 | Power and Electrical Engineering