Navigation Links
'Vicious circle' offers new acute leukemia treatment target
Date:4/13/2010

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

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 NFĸB and Sp1.


'/>"/>

Contact: Darrell E. Ward
Darrell.Ward@osumc.edu
614-293-3737
Ohio State University Medical Center
Source:Eurekalert

Related biology news :

1. Tall tale of giant stingray circles the globe
2. Nations largest organization of ecologists offers expert database
3. Fertility industry offers big money to recruit desirable egg donors at top universities
4. DNA nanotechnology breakthrough offers promising applications in medicine
5. New microscopy technique offers close-up, real-time view of cellular phenomena
6. Society of Interventional Radiology Press offers new edition of patient care resource
7. The sea squirt offers hope for Alzheimers sufferers
8. TriCipher myOneLogin SignatureBook Offers Digital Signatures On-Demand
9. Brain study offers insight into causes of autism
10. Synthetic biology offers new opportunities for interdisciplinary collaboration
11. Society of Interventional Radiology hosts oncology therapies Webinar, offers resources
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/9/2016)... an innovation leader in attendance control systems is proud to announce the introduction of ... make sure the right employees are actually signing in, and to even control the ... ... ... ...
(Date:6/2/2016)... LONDON , June 2, 2016 ... has awarded the 44 million US Dollar project, ... Security Embossed Vehicle Plates including Personalization, Enrolment, and IT Infrastructure ... world leader in the production and implementation of Identity Management ... in January, however Decatur was selected ...
(Date:5/24/2016)... Ampronix facilitates superior patient care by providing unparalleled technology to leaders of ... the latest premium product recently added to the range of products distributed by Ampronix. ... ... ... Medical Display- Ampronix News ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... ... June 23, 2016 , ... Charm Sciences, Inc. is pleased ... received AOAC Research Institute approval 061601. , “This is another AOAC-RI approval of ... Salter, Vice President of Regulatory and Industrial Affairs. “The Peel Plate methods perform ...
(Date:6/23/2016)... ... June 23, 2016 , ... Supplyframe, ... of the Supplyframe Design Lab . Located in Pasadena, Calif., the Design ... of how hardware projects are designed, built and brought to market. , The ...
(Date:6/23/2016)... June 23, 2016  Blueprint Bio, a company dedicated ... the medical community, has closed its Series A funding ... . "We have received a commitment from ... we need to meet our current goals," stated ... the runway to complete validation on the current projects ...
(Date:6/23/2016)... ... June 23, 2016 , ... ... and technical consulting, provides a free webinar on Performing Quality Investigations: ... 2016 at 12pm CT at no charge. , Incomplete investigations are still a ...
Breaking Biology Technology: