Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Leukemia gene normally has mammary gland function

21.07.2006
St. Jude team discovers gene that triggers highly lethal type of leukemia is also gene that regulates mammary gland function during nursing

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!
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Engineers program tiny robots to move, think like insects

15.12.2017 | Power and Electrical Engineering

One in 5 materials chemistry papers may be wrong, study suggests

15.12.2017 | Materials Sciences

New antbird species discovered in Peru by LSU ornithologists

15.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>