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:6/3/2016)... 3, 2016 Das ... Nepal hat ein 44 ... geprägter Kennzeichen, einschließlich Personalisierung, Registrierung und IT-Infrastruktur, ... Produktion und Implementierung von Identitätsmanagementlösungen. Zahlreiche renommierte ... Januar teilgenommen, aber Decatur wurde als konformste ...
(Date:6/2/2016)... Perimeter Surveillance & Detection Systems, Biometrics & ... & Other Service  The latest report from ... of the global Border Security market . Visiongain ... billion in 2016. Now: In November 2015 ... and hardware technologies for advanced video surveillance. ...
(Date:5/20/2016)... May 20, 2016  VoiceIt is excited to ... VoicePass. By working together, VoiceIt and ... VoiceIt and VoicePass take slightly different approaches to ... both security and usability. ... this new partnership. "This marketing and ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... ... June 27, 2016 , ... Cancer ... what they believe could be a new and helpful biomarker for malignant pleural ... Click here to read it now. , Biomarkers are components in the ...
(Date:6/27/2016)... June 27, 2016   Ginkgo Bioworks , a ... engineering, was today awarded as one of the ... the world,s most innovative companies. Ginkgo Bioworks is ... the real world in the nutrition, health and ... directly with customers including Fortune 500 companies to ...
(Date:6/23/2016)... ... June 23, 2016 , ... ... of its second eBook, “Clinical Trials Patient Recruitment and Retention Tips.” Partnering with ... in this eBook by providing practical tips, tools, and strategies for clinical researchers. ...
(Date:6/23/2016)... HOUSTON , June 23, 2016 ... agreement with the Cy-Fair Sports Association to serve ... of the agreement, Houston Methodist Willowbrook will provide ... education and connectivity with association coaches, volunteers, athletes ... partner with the Cy-Fair Sports Association and to ...
Breaking Biology Technology: