Featured Research

from universities, journals, and other organizations

'Vicious circle' offers new acute leukemia treatment target

Date:
April 21, 2010
Source:
Ohio State University Medical Center
Summary:
Researchers have discovered a network of protein and microRNA molecules that, when imbalanced, contributes to abnormally high levels of a protein called KIT and favors the development of acute myeloid leukemia (AML). The researchers therapeutically targeted this network in mice and forced the disease into remission. They believe that targeting this mechanism and reducing the amount of KIT protein will prove to be a more effective therapy for AML than the current standard of care.

Researchers have identified a self-feeding "vicious circle" of molecules that keeps acute leukemia cells alive and growing and that drives the disease forward.

Related Articles


The findings suggest a new strategy for treating acute myeloid leukemia (AML), one that targets this molecular network and lowers the amount of a protein called KIT, say researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) who conducted the study.

Published in the April 13 issue of the journal Cancer Cell, the study described a new network of protein and microRNA molecules that, when imbalanced, contributes to abnormal KIT protein abundance and favors leukemia development. The researchers were also able to target this network with therapeutic drugs.

"We now understand the mechanism responsible for making so much KIT protein in AML cells, and we believe that targeting that mechanism and reducing the amount of that protein will prove to be a more effective therapy for this disease than the current standard of care," says study leader Dr. Guido Marcucci, professor of internal medicine and an AML specialist at the OSUCCC-James.

AML strikes 12,800 Americans, killing 9,000 of them each year. More than 80 percent of those cases have elevated levels of KIT protein.

Currently, doctors treat AML using standard chemotherapy. Drugs that target and block the activity of the KIT protein are being tested in clinical trials. These agents, called tyrosine kinase inhibitors, bind to the protein and stop disease progression, but they can lose their effectiveness when new mutations that arise during the course of the disease alter the protein.

"Our study suggests that the amount of KIT protein in cancer cells is as important as its activity, and we discovered that the amount of the protein is controlled by a circular network of molecules that has many points of entry," says senior co-leader Dr. Ramiro Garzon, assistant professor of internal medicine and an AML specialist at the OSUCCC-James.

"These findings provide a strong rationale for the use and development of drugs that target the components of this network rather than focusing on the activity of KIT alone."

Marcucci, Garzon, first author Shujun Liu, assistant professor of internal medicine, and their colleagues began this study by showing that patients with mutations in the KIT gene in their leukemic cells had the highest levels of the KIT protein in those cells, and that these patients also had the poorest survival.

"This told us that the amount of the protein in cancer cells is important to the disease process," Liu says.

Using laboratory-grown AML cells, the researchers identified the series of molecules that control the amount of KIT protein, showing for the first time that a microRNA called miR-29b, along with several well-known cancer-related genes, regulate KIT production.

Normally, these elements work in a balanced fashion to produce the correct amount of KIT protein for healthy cell survival and proliferation. That normal balance is derailed when gene mutations or other genetic damage occurs in the network and promotes the overproduction of the KIT protein.

"It becomes a vicious circle because no matter where genetic damage occurs, the result is the same -- overactivation of the circle, overexpression of the KIT protein, and proliferation of leukemic cells," Liu says.

Using a mouse model, the researchers showed that raising the amount of mutated KIT protein causes leukemia, and drugs that target the network lower the amount of that protein and drive the leukemia into remission. These drugs included proteasome inhibitors, histone deacetylase inhibitors, along with inhibitors of molecules called NF?B and Sp1.

Funding from the National Cancer Institute, the Harry T. Mangurian Jr. Foundation Leukemia Research Fund, the Coleman Leukemia Research Foundation, the Sidney Kimmel Cancer Research Foundation, and the Deutsche Krebshilfe (Dr. Mildred Scheel Foundation for Cancer Research) supported this research.

Other Ohio State researchers involved in this study were Lai-Chu Wu, Jiuxia Pang, Ramasamy Santhanam, Sebastian Schwind, Yue-Zhong Wu, Christopher Hickey, Jianhua Yu, Heiko Becker, Kati Maharry, Michael D. Radmacher, Chenglong Li, Susan P. Whitman, Anjali Mishra, Nicole Stauffer, Anna M. Eiring, Roger Briesewitz, Robert A. Baiocchi, Kenneth K. Chan, Michael A. Caligiuri, John C. Byrd, Carlo M. Croce, Clara D. Bloomfield and Danilo Perrotti.


Story Source:

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


Journal Reference:

  1. Liu et al. Sp1/NFκB/HDAC/miR-29b Regulatory Network in KIT-Driven Myeloid Leukemia. Cancer Cell, 2010; 17 (4): 333 DOI: 10.1016/j.ccr.2010.03.008

Cite This Page:

Ohio State University Medical Center. "'Vicious circle' offers new acute leukemia treatment target." ScienceDaily. ScienceDaily, 21 April 2010. <www.sciencedaily.com/releases/2010/04/100413160905.htm>.
Ohio State University Medical Center. (2010, April 21). 'Vicious circle' offers new acute leukemia treatment target. ScienceDaily. Retrieved November 26, 2014 from www.sciencedaily.com/releases/2010/04/100413160905.htm
Ohio State University Medical Center. "'Vicious circle' offers new acute leukemia treatment target." ScienceDaily. www.sciencedaily.com/releases/2010/04/100413160905.htm (accessed November 26, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Wednesday, November 26, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

Newsy (Nov. 25, 2014) — The US FDA is announcing new calorie rules on Tuesday that will require everywhere from theaters to vending machines to include calorie counts. Video provided by Newsy
Powered by NewsLook.com
Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Newsy (Nov. 25, 2014) — Need another reason to eat yogurt every day? Researchers now say it could reduce a person's risk of developing type 2 diabetes. Video provided by Newsy
Powered by NewsLook.com
Madagascar Working to Contain Plague Outbreak

Madagascar Working to Contain Plague Outbreak

AFP (Nov. 24, 2014) — Madagascar said Monday it is trying to contain an outbreak of plague -- similar to the Black Death that swept Medieval Europe -- that has killed 40 people and is spreading to the capital Antananarivo. Duration: 00:42 Video provided by AFP
Powered by NewsLook.com
Are Female Bosses More Likely To Be Depressed?

Are Female Bosses More Likely To Be Depressed?

Newsy (Nov. 24, 2014) — A new study links greater authority with increased depressive symptoms among women in the workplace. Video provided by Newsy
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:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

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