Featured Research

from universities, journals, and other organizations

How a mutated protein outwits evolution and fuels leukemia

Date:
June 20, 2013
Source:
NYU Langone Medical Center
Summary:
Scientists have discovered the survival secret to a genetic mutation that stokes leukemia cells, solving an evolutionary riddle and paving the way to a highly targeted therapy for leukemia. A new article describe how a mutated protein, called Fbxw7, behaves differently when expressed in cancer cells versus healthy cells.

Scientists have discovered the survival secret to a genetic mutation that stokes leukemia cells, solving an evolutionary riddle and paving the way to a highly targeted therapy for leukemia. In a paper published today in Cell, researchers at NYU Langone Medical Center describe how a mutated protein, called Fbxw7, behaves differently when expressed in cancer cells versus healthy cells. "Fbxw7 is essential for making blood cells, so the big mystery is why a mutation on a gene so important for survival would persist," says lead author Iannis Aifantis, PhD, chair of pathology at NYU Langone Medical Center and an Early Career Scientist at Howard Hughes Medical Institute. "What we've found is that the mutation affects cancerous cells but not healthy cells."

The Fbxw7 protein regulates the production of so-called hematopoietic stem cells, precursors that give rise to all types of blood cells. Without Fbxw7, the body loses the ability to produce blood and eventually succumbs to anemia. Scientists are only beginning to understand why mutated Fbxw7 appears in a significant portion of human tumors, including gastric, prostate, and some breast cancers. The mutation is especially prevalent in T-cell acute lymphoblastic leukemia, or T-ALL, a rare but lethal type of pediatric leukemia that causes the over-production of immature white blood cells.

In their experiments, Dr. Aifantis, working in collaboration with graduate student Bryan King and others, began by introducing mutated Fbxw7 into healthy blood stem cells in mice. "We thought the mutation would induce anemia, just as it does when Fbxw7 is deleted," says Dr. Aifantis. But to the researchers' surprise, nothing happened -- the stem cells continued to manufacture blood cells.

When the researchers then introduced in mice the mutated Fbxw7 into leukemic blood stem cells -- those that overproduce white blood cells and cause leukemia -- the cancer accelerated. "We found that the mutation made leukemia stem cells much more aggressive," Dr. Aifantis says.

In follow-up experiments, the researchers showed that Fbxw7 binds to and degrades a protein called Myc, which fuels leukemic stem cells, and has long been associated with many other cancers and the recurrence of cancer after treatment. When Fbxw7 is mutated, Myc is left unchecked, they found, and the population of cancer stem cells swells. This insight also helps explain why healthy blood stem cells seem to "ignore" mutated Fbxw7. Unlike leukemic stem cells, healthy blood stem cells typically lie dormant until the body requires an emergency supply of blood and they rarely express Myc. "Normal blood stem cells express very little Myc because they are not cycling. A mutation does not affect the substrate because the substrate does not exist," says Dr. Aifantis. "Leukemia stem cells, however, do express Myc and Fbxw7 mutations increase its abundance."

The researchers then wondered if eliminating Myc could potentially block leukemia. Indeed, deleting the Myc gene in mice with leukemia depleted leukemic stem cells and stopped the growth of tumors. They achieved the same results in mice and human cell and bone marrow samples of T-ALL using a new class of cancer drug called a BET inhibitor that blocks Myc. "We found that the BET inhibitor could actually kill leukemia stem cells. And without stem cells, the leukemia simply cannot grow," says Dr. Aifantis.

The researchers believe they can use the BET inhibitor to target pediatric and adult T-ALL leukemia. This work was supported by a grant from the National Cancer Institute.


Story Source:

The above story is based on materials provided by NYU Langone Medical Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Bryan King, Thomas Trimarchi, Linsey Reavie, Luyao Xu, Jasper Mullenders, Panagiotis Ntziachristos, Beatriz Aranda-Orgilles, Arianne Perez-Garcia, Junwei Shi, Christopher Vakoc, Peter Sandy, StevenS. Shen, Adolfo Ferrando, Iannis Aifantis. The Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability. Cell, 2013; 153 (7): 1552 DOI: 10.1016/j.cell.2013.05.041

Cite This Page:

NYU Langone Medical Center. "How a mutated protein outwits evolution and fuels leukemia." ScienceDaily. ScienceDaily, 20 June 2013. <www.sciencedaily.com/releases/2013/06/130620142852.htm>.
NYU Langone Medical Center. (2013, June 20). How a mutated protein outwits evolution and fuels leukemia. ScienceDaily. Retrieved July 28, 2014 from www.sciencedaily.com/releases/2013/06/130620142852.htm
NYU Langone Medical Center. "How a mutated protein outwits evolution and fuels leukemia." ScienceDaily. www.sciencedaily.com/releases/2013/06/130620142852.htm (accessed July 28, 2014).

Share This




More Health & Medicine News

Monday, July 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Deadly Ebola Virus Threatens West Africa

Deadly Ebola Virus Threatens West Africa

AP (July 28, 2014) West African nations and international health organizations are working to contain the largest Ebola outbreak in history. It's one of the deadliest diseases known to man, but the CDC says it's unlikely to spread in the U.S. (July 28) Video provided by AP
Powered by NewsLook.com
$15B Deal on Vets' Health Care Reached

$15B Deal on Vets' Health Care Reached

AP (July 28, 2014) A bipartisan deal to improve veterans health care would authorize at least $15 billion in emergency spending to fix a veterans program scandalized by long patient wait times and falsified records. (July 28) Video provided by AP
Powered by NewsLook.com
Two Americans Contract Ebola in Liberia

Two Americans Contract Ebola in Liberia

Reuters - US Online Video (July 28, 2014) Two American aid workers in Liberia test positive for Ebola while working to combat the deadliest outbreak of the virus ever. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
Traditional African Dishes Teach Healthy Eating

Traditional African Dishes Teach Healthy Eating

AP (July 28, 2014) Classes are being offered nationwide to encourage African Americans to learn about cooking fresh foods based on traditional African cuisine. The program is trying to combat obesity, heart disease and other ailments often linked to diet. (July 28) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins