Nav: Home

Solving the mystery of NPM1 in acute myeloid leukemia

November 13, 2018

While it has long been recognized that mutated gene NPM1 plays an important role in acute myeloid leukemia, no one has determined how the normal and the mutated forms of the protein NPM1 function.

"It is one of the biggest enigmas in acute myeloid leukemia," said Dr. Margaret Goodell, professor in the Center for Stem Cells and Regenerative Medicine and in the Departments of Pediatrics and Molecular and Human Genetics at Baylor, and senior author of the paper. "The most common mutations associated with acute myeloid leukemia occur within the NPM1 gene; however, no mechanism of action has been uncovered to date."

The team developed new strategies to exploit CRISPR technology to readily target and manipulate solely the mutant form of the protein, also called NPM1c, leaving the rest of the cell intact. This enabled the research team to unlock its function. The team found that by blocking the export of mutant NPM1 from the nucleus to the cytoplasm using either CRISPR or an available cancer drug that interferes with the exporter, such as XPO1, they were able to inhibit leukemic cell growth. In culture dishes, leukemic cells disappeared, and mice with leukemia treated with the drug lived longer.

"We found that when the NPM1 protein is allowed to leave the nucleus, it activates a set of genes that drive growth of leukemia. If NPM1c can be prevented from entering the cytoplasm, acute myeloid leukemia cells will differentiate or die and cease to repopulate as cancerous cells," said Dr. Lorenzo Brunetti, postdoctoral associate in the Goodell Lab at Baylor and co-first author of the paper.

These findings show that acute myeloid leukemia cells expressing the NPM1-mutant are highly dependent on continued export of NPM1c to proliferate and provides a rationale for the use of nuclear export inhibitor therapeutics in NPM1-mutated AML.

"This research has profound therapeutic implications," Brunetti said. "There is already a drug available that inhibits the export of multiple proteins, including mutant NPM1, from the nucleus to the cytoplasm. This gives us reasonable evidence that we can treat this type of AML with an existing therapy. We hope this research opens the door for larger conversations and continued research to spur a clinical trial."

"We were able to answer a burning question in the AML field by exploiting recent technical advances in CRISPR/Cas9 methodologies. Dr. Brunetti and I found this project to be an ideal complement for our respective experiences and interests, and the environment at Baylor allowed us to pursue this project with input and support from faculty across multiple departments," said Michael Gundry, M.D./Ph.D. student in the Medical Scientist Training Program at Baylor and co-first author of the paper.
-end-
Interested in all the details about this study? Read the paper published in the journal Cancer Cell.

For a full list of contributors and their affiliations, visit this link. This study was funded by the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, the Associazione Italiana per la Ricerca sul Cancro, the European Research Council, the Leukemia and Lymphoma Society, the American Cancer Society, the Claudia Adams Barr Program in Innovative Basic Cancer Research and the Damon Runyon Cancer Research Foundation.

Baylor College of Medicine

Related Leukemia Articles:

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.
Finding second hits to knock out leukemia
Targeted drugs are a cornerstone of personalized medicine, yet come with important drawbacks.
Understanding the emergence of leukemia
Acute T-cell lymphoblastic leukemia is a rare type of blood cancer that affects mostly children.
New treatment approach for leukemia
An international research team led by researchers from Vetmeduni Vienna have made an important discovery that could lead to a better understanding of lymphocytic leukemia.
More Leukemia News and Leukemia Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.