Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Overlooked molecular machine in cell nucleus may hold key to treating aggressive leukemia

23.04.2019

Spliceosome misconnects generate mutant gene/protein that fuel cancerous cells

Many individuals forced to fight an exceptionally aggressive form of the blood cancer acute myeloid leukemia (AML) don't survive more than five years.


This image shows leukemia cells that scientists studied to identify potential treatment targets for a very aggressive form of the blood cancer, acute myeloid leukemia (AML). Researchers report in Nature Cell Biology they found a hyperactive form of a protein called IRAK4 that sends cells on a cancer-causing frenzy, which may hold a key to treating a subset of people with the disease.

Credit: Cincinnati Children's

The only cure--a bone marrow transplant--often isn't suitable for these very sick patients. Now, an international team of scientists report in Nature Cell Biology on a long-overlooked part of a leukemic cell's internal machinery called the spliceosome, where they found a hyperactive form of a protein called IRAK4 that sends cells on a cancer-causing frenzy.

When they targeted the hyperactive form of IRAK4 in laboratory tests to block its function in AML cells, and in patient AML cells transplanted into immunosuppressed mice, the experimental treatment led to a significant reduction of the leukemic cells.

It also prolonged survival in the animal models, according to Daniel Starczynowski, PhD, the multi-institutional study's senior investigator and part of the Cancer and Blood Diseases Institute at Cincinnati Children's Hospital Medical Center.

In this study and other projects in the lab, Starczynowki and colleagues are testing existing drugs that can target hyperactive IRAK4 in leukemia cells. They also are developing a prospective drug that more effectively inhibits hyperactive IRAK4 to treat AML and its precursor disease, myelodysplastic syndromes (MDS).

Starczynowski said that with additional preclinical research and development, the researchers would like within a few years to have their still-unnamed IRAK4 inhibitor ready for initial clinical tests in AML patients. The need for new treatments is urgent, he said.

"There is very little we can do for these patients. Even new drugs now getting fast-tracked through the development process may only produce another six months of survival," Starczynowski said. "The curative option is a bone marrow transplant, but most of these patients don't qualify. The field is really desperate for something that can help these patients."

The findings in this study, including use of IRAK4-inhibiting drugs, would potentially affect a subset of about 20 percent of AML-MDS patients, according to researchers. But that's significant, they say. Now that they know to look more closely at this seemingly obscure, tiny molecular machine in the cell's nucleus--the spliceosome--it creates a way to find genetic coding miscues that fuel other subsets of AML that also depend on a hyperactive IRAK4.

Sequencing in the Spliceosome

Although invisible to the naked eye, the spliceosome is important. In a process of dicing and splicing, the spliceosome edits out unnecessary snippets of RNA coding called introns or exons. It then splices the loose snipped ends of RNA back together so specific proteins will do their jobs correctly.

But in AML cells, there are mutations in a gene call U2AF1, which result in RNA splicing errors. When U2AF1 functions normally, the correct snipped ends of RNA are glued back together. But when a mutated form of U2AF1 produces incorrectly formed RNA molecules of IRAK4, it results in a version of IRAK4 protein with extra coding sequences called IRAK4-L (or long). Together they hijack the innate immune system's molecular processes and trigger oncogenesis in myeloid blood cells.

Global Effort

Including first author Molly Smith, a graduate student and member of the Starczynowski lab, the study was a collaboration of eight institutions in the U.S. and the University of Oxford in England. The focus on IRAK4 started over five years ago when Cincinnati Children's cancer biologist Kakajan Komurov--working on a separate research project--noticed that every time he analyzed cancerous cells from patients, he saw high levels of the IRAK4 protein with extra coding sequences.

After Komurov shared his observation with Starczynowski during a chance corridor encounter at work, they launched a new project that went on to include Cincinnati Children's bioinformatician Nathan Salomonis, PhD, and Gaurav Choudhary, PhD, and Amit Verma, MD, at the Albert Einstein College of Medicine in Bronx, NY.

Also collaborating are investigators from the National Institutes of Health (NIH), the University of Cincinnati, and the Department of Medicine at Washington University in St. Louis.

Together the team was able to combine biological testing of leukemia models in the lab and a global analysis of genetic sequencing data by using bioinformatics and systems biology. They also were able to analyze data from the NIH's massive Cancer Genome Atlas, essentially a digital encyclopedia of all the genes (and the known related processes) linked to cancer.

Because the preclinical results are from experiments in cell lines and mouse models, the researchers are careful to emphasize their findings may not translate clinically to human patients. Still, the researchers say they're encouraged to have come far enough that the design of new and potentially effective targeted therapies is well underway for a blood cancer that has few such options.

###

The study will be available at this link after it publishes online.

Funding support for the study came from: the Cincinnati Children's Hospital Research Foundation, the Leukemia Lymphoma Society, the NIH (R35HL135787, RO1DK102759, RO1DK113639, F31HL132420), grants from the Edward P. Evans Foundation, and a grant from Bloodwise (#13042).

Nick Miller | EurekAlert!
Further information:
http://dx.doi.org/10.1038/s41556-019-0314-5

Further reports about: AML RNA blood cancer bone marrow cell nucleus hyperactive leukemia

More articles from Life Sciences:

nachricht A human liver cell atlas
15.07.2019 | Max Planck Institute of Immunobiology and Epigenetics

nachricht Researchers reveal mechanisms for regulating temperature sensitivity of soil organic matter decompos
15.07.2019 | Chinese Academy of Sciences Headquarters

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Artificial neural network resolves puzzles from condensed matter physics: Which is the perfect quantum theory?

For some phenomena in quantum many-body physics several competing theories exist. But which of them describes a quantum phenomenon best? A team of researchers from the Technical University of Munich (TUM) and Harvard University in the United States has now successfully deployed artificial neural networks for image analysis of quantum systems.

Is that a dog or a cat? Such a classification is a prime example of machine learning: artificial neural networks can be trained to analyze images by looking...

Im Focus: Extremely hard yet metallically conductive: Bayreuth researchers develop novel material with high-tech prospects

An international research group led by scientists from the University of Bayreuth has produced a previously unknown material: Rhenium nitride pernitride. Thanks to combining properties that were previously considered incompatible, it looks set to become highly attractive for technological applications. Indeed, it is a super-hard metallic conductor that can withstand extremely high pressures like a diamond. A process now developed in Bayreuth opens up the possibility of producing rhenium nitride pernitride and other technologically interesting materials in sufficiently large quantity for their properties characterisation. The new findings are presented in "Nature Communications".

The possibility of finding a compound that was metallically conductive, super-hard, and ultra-incompressible was long considered unlikely in science. It was...

Im Focus: Modelling leads to the optimum size for platinum fuel cell catalysts: Activity of fuel cell catalysts doubled

An interdisciplinary research team at the Technical University of Munich (TUM) has built platinum nanoparticles for catalysis in fuel cells: The new size-optimized catalysts are twice as good as the best process commercially available today.

Fuel cells may well replace batteries as the power source for electric cars. They consume hydrogen, a gas which could be produced for example using surplus...

Im Focus: The secret of mushroom colors

Mushrooms: Darker fruiting bodies in cold climates

The fly agaric with its red hat is perhaps the most evocative of the diverse and variously colored mushroom species. Hitherto, the purpose of these colors was...

Im Focus: First results of the new Alphatrap experiment

Physicists at the Max Planck Institute for Nuclear Physics in Heidelberg report the first result of the new Alphatrap experiment. They measured the bound-electron g-factor of highly charged (boron-like) argon ions with unprecedented precision of 9 digits. In comparison with a new highly accurate quantum electrodynamic calculation they found an excellent agreement on a level of 7 digits. This paves the way for sensitive tests of QED in strong fields like precision measurements of the fine structure constant α as well as the detection of possible signatures of new physics. [Physical Review Letters, 27 June 2019]

Quantum electrodynamics (QED) describes the interaction of charged particles with electromagnetic fields and is the most precisely tested physical theory. It...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on UV LED Technologies & Applications – ICULTA 2020 | Call for Abstracts

24.06.2019 | Event News

SEMANTiCS 2019 brings together industry leaders and data scientists in Karlsruhe

29.04.2019 | Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

 
Latest News

A human liver cell atlas

15.07.2019 | Life Sciences

No more trial-and-error when choosing an electrolyte for metal-air batteries

15.07.2019 | Power and Electrical Engineering

Possibilities of the biosimilar principle of learning are shown for a memristor-based neural network

15.07.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>