How an interest in bipolar disorder drugs led to a better understanding of leukemia

October 31, 2017

A research project that began 20 years ago with an interest in how lithium treats mood disorders has yielded insights into the progression of blood cancers such as leukemia. The research, which centers on a protein called GSK-3, will be published in the Nov. 3 issue of the Journal of Biological Chemistry.

Lithium is considered a highly effective treatment for bipolar disorder and other mood disorders, but it still works in only a fraction of patients and has a number of side effects. Furthermore, its mechanism of action is poorly understood, hampering efforts to improve on it.

In 1996, Peter Klein of the University of Pennsylvania discovered that one of lithium's biological activities was inhibiting GSK-3, an enzyme that modifies other proteins by attaching phosphate molecules, a process called phosphorylation. Lithium's effect on GSK-3 affected the development of animal cells, but it is still unknown what connection, if any, this has to psychiatric disease.

Since then, Klein - now a professor of medicine at the University of Pennsylvania - has been investigating many different aspects of GSK-3 activity. "In this paper, we were trying to find out what proteins in the cell are affected by GSK-3 inhibition," Klein said. "We compared cells with GSK-3 to cells completely lacking GSK-3 to ask how other proteins changed."

"Mood disorders are so multifaceted in terms of the pathways and pathologies involved; it's really difficult to pin down a specific pathway," said Mansi Shinde, a former graduate student in Klein's research group who led the new study. "We said: Let's look at what GSK-3 does, and that would maybe lead us toward what lithium does."

The research team used mass spectrometry to compare phosphorylation of proteins from mouse embryonic stem cells with fully functioning GSK-3 to cells in which the gene encoding GSK-3 had been deleted. The resulting massive dataset is called a phosphoproteome - a comprehensive catalog of proteins that are phosphorylated by GSK-3. Analyzing the data yielded some surprising findings.

Conventional wisdom had suggested that GSK-3 phosphorylates proteins that contain a specific amino acid sequence, but the new phosphoproteome showed that the majority of proteins whose phosphorylation depended on GSK-3 did not contain this sequence. Notably, the phosphorylated proteins included a group called splicing factors, which splice together different sections of messenger RNA, changing the proteins that they encode. Absence of GSK-3 changed the splicing patterns of more than 200 messenger RNAs.

The finding that GSK-3 could affect RNA splicing pointed to an unexpected connection: leukemia. Several factors newly discovered to be phosphorylated by GSK-3 are also known to be mutated in acute myeloid leukemia, a condition in which aberrant splicing causes uncontrolled white blood cell proliferation. This observation could also explain why one of the side effects of taking lithium is increased white blood cell count.

"The effect on the splicing factors and other mutations associated with leukemia was completely surprising to me," Klein said. The group is therefore now pursuing investigations into how GSK-3 affects the growth of healthy and leukemic blood cells.

Shinde and Klein are not yet sure whether GSK-3's effect on RNA splicing explains its role in mood disorders. The effect of GSK-3 on messenger RNA in neuronal cells, with or without lithium, would need to be examined to determine this. The study underlines how investigations into the basic biological function of a drug target can lead in unexpected directions. "[The GSK-3 phosphoproteome] is a really large data set," Shinde said. "It's a resource for the field." "The relevance to leukemia could be direct and something worthy of immediate study," Klein said. "The role in psychiatric disorders is a major interest of the work, but the impact would be down the road, not immediate."
-end-
The research was funded by the National Institutes of Health and the University of Pennsylvania.

About the Journal of Biological Chemistry

JBC is a weekly peer-reviewed scientific journal that publishes research "motivated by biology, enabled by chemistry" across all areas of biochemistry and molecular biology. The read the latest research in JBC, visit http://www.jbc.org/.

About the American Society for Biochemistry and Molecular Biology

The ASBMB is a nonprofit scientific and educational organization with more than 12,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, at nonprofit research institutions and in industry. The Society's student members attend undergraduate or graduate institutions. For more information about ASBMB, visit http://www.asbmb.org.

American Society for Biochemistry and Molecular Biology

Related Leukemia Articles from Brightsurf:

New therapeutic approach against leukemia
Using an RNA molecule complex, researchers can prevent retention of cancer stem cell in their tumor supporting niche

Nanoparticle for overcoming leukemia treatment resistance
One of the largest problems with cancer treatment is the development of resistance to anticancer therapies.

Key gene in leukemia discovered
Acute myeloid leukemia (AML) is one of the most common forms of blood cancer among adults and is associated with a low survival rate, and leads to the inhibition of normal blood formation.

Vitamin B6, leukemia's deadly addiction
Researchers from CSHL and Memorial Sloan Kettering Cancer Center have discovered how Acute Myeloid Leukemia is addicted to vitamin B6.

Artificial intelligence tracks down leukemia
Artificial intelligence can detect one of the most common forms of blood cancer - acute myeloid leukemia -- with high reliability.

Milestone reached in new leukemia drug
Using a chemical compound called YKL-05-099, a team of cancer researchers from CSHL and the Dana Farber Institute was able to target the Salt-Inducible Kinase 3 (SIK3) pathway and extend survival in mice with MLL leukemia.

The drug combination effective against bovine leukemia
Scientists have succeeded in reducing levels of the bovine leukemia virus (BLV) in cows with severe infections by combining an immune checkpoint inhibitor and an enzyme inhibitor.

Towards a safer treatment for leukemia
An international team of researchers at VIB-KU Leuven, Belgium, the UK Dementia Institute and the Children's Cancer Institute, Australia, have found a safer treatment for a specific type of leukemia.

Research paves way for new source for leukemia drug
Chemistry researchers have patented a method for making anti-leukemia compounds that until now have only been available via an Asian tree that produces them.

An atlas of an aggressive leukemia
A team of researchers led by Bradley Bernstein at the Ludwig Center at Harvard has used single-cell technologies and machine learning to create a detailed 'atlas of cell states' for acute myeloid leukemia (AML) that could help improve treatment of the aggressive cancer.

Read More: Leukemia News and Leukemia Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.