In a current study, Dr. Marina Scheller (now at the University Hospital Hamburg-Eppendorf) and Professor Achim Leutz report that these two processes in CML – disease progression and drug resistance – are directly associated with each other due to crosstalk between two cellular signaling pathways.
Their findings may lead to new strategies for developing combination treatments to halt the progression of the disease (Journal of Experimental Medicine, doi:10.1084/jem.20130706)*.
In CML, the white blood cells (leukocytes) multiply in an uncontrolled fashion. This is caused by a mutation in the DNA of a single blood stem cell. In this mutation, parts of chromosome 9 fuse with parts of chromosome 22. This discovery was made in 1960 and termed the “Philadelphia chromosome” after the place it was discovered in the U.S. The product of the Philadelphia chromosome is the BCR-ABL oncogene. The protein product of this BCR-ABL gene is a tyrosine kinase which is responsible for the excessive proliferation of the white blood cells and for triggering the progression of chronic myeloid leukemia.
About 15 years ago a novel drug (imatinib) was developed that can block the tyrosine kinase produced by the Philadelphia chromosome. With imatinib, which has been used since 2001, the disease can be suppressed in the majority of CML patients.
However, with increasing duration of the disease, leukemia cells can develop resistance to imatinib, and the drug treatment can lose its effectiveness in some of the patients. A consequence is the emergence of the so-called blast crisis in which the blood of the patients is flooded with immature white blood cells (blasts). This phase is life-threatening because drug treatment is usually unsuccessful. Many CML experts attribute the disease progression to changes in the so-called “leukemia stem cells”. Thus, to prevent disease relapse, researchers across the globe are seeking to decipher the disease mechanisms and to develop new treatment options to eliminate these highly malignant leukemia stem cells.
Two signaling pathways under scrutiny
The molecular mechanism of CML progression identified by the MDC cancer researchers may aid in targeting these complications directly. In their study, Dr. Scheller and Professor Leutz focused on two signaling pathways. One is the Wnt signaling pathway with its main component, the protein beta-catenin. Of the two pathways, Wnt has thus far been more extensively studied. Normally, it is critical for the regulation of embryonic cells. If this signaling pathway is erroneously activated, various types of cancer can arise. Wnt signaling also plays an important role in triggering a blast crisis in CML.
The cancer researchers also focused on the interferon signaling pathway, and particularly on the function of the interferon regulatory factor 8 (Irf8). Irf8 protects against infection and regulates the production of a specific type of white blood cells, the granulocytes. It is also known that Irf8 counteracts the BCR-ABL oncoprotein and may suppress the development of cancer.
For several years scientists have known that in patients with CML, the tumor suppressor function of Irf8 is weakened, whereas beta-catenin and the Wnt signaling are active. Until now it was unclear why this is so. The MDC researchers were now able to show that both phenomena are directly related to each other and that the BCR-ABL oncogene product of the Philadelphia chromosome takes over the control of both pathways.
“The Philadelphia chromosome inhibits the tumor suppressor Ifr8. The suppression of Irf8 activity promotes the development of CML. But the suppression of Irf8 alone is not sufficient to trigger a blast crisis,” said Professor Leutz. “What is crucial is the activity of the beta-catenin protein. Beta-catenin is the amplifier of the misguided cell differentiation and cell division. Beta-catenin activation speeds up the uncontrolled growth of the white blood cells and prevents their maturation into functional granulocytes,” he added.
“We were able to demonstrate that the loss of the interferon regulatory factor 8 (Irf8) and the subsequent activation of the Wnt/beta-catenin signaling pathway lead to an aggressive behavior of the CML stem cell with the BCR-ABL gene,” the authors of the study summarized their findings. According to the cancer researchers, precisely these two changes in the leukemia stem cell, suppression of Ifr8 and activation of beta-catenin, are part of the fact that imatinib and related drugs lose their effectiveness and help the leukemia stem cells to survive.
Professor Leutz also pointed out that before the drug imatinib existed, CML was also treated with interferon-alpha (IFN-alpha). Interferon-alpha induces an increase in Ifr8 proteins and simultaneously an improved response to imatinib. “When there is a relapse,” he said, “it may be advantageous to additionally increase Irf8 and to suppress the deregulated beta-catenin.” In the laboratory, Professor Leutz and his team have already achieved this objective in mice.
*Crosstalk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance
Marina Scheller*1,2, Jörg Schönheit1, Karin Zimmermann3, Ulf Leser3, Frank Rosenbauer4 and Achim Leutz*1,2
1Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany.
2Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
3Institute for Computer Science, Humboldt-University of Berlin, Unter den Linden 6, 10099 Berlin, Germany.
4Institute of Molecular Tumor Biology - IMTB, Medical Faculty of the University of Muenster, Robert-Koch-Str. 43, 48149, Münster, Germany.
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
13125 Berlin, Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
Barbara Bachtler | Source: Max-Delbrück-Centrum
Further information: www.mdc-berlin.de/
Further Reports about: blood cell > cancer research > Cancer treatment > chronic insomnia > CML > Drug Delivery > drug treatment > leukemia > MDC > Medicine > Molecular Target > myeloid > Parkinson’s Disease > regulatory factor > signaling pathway > stem cells > tumor suppressor > white blood cell
More articles from Health and Medicine:
Antibiotic-resistant typhoid likely to spread despite drug control program
10.12.2013 | Wellcome Trust
Targeted treatment can significantly reduce relapse in children with AML leukemia
09.12.2013 | Children's Mercy Hospital
Researchers from Brown University and the University of Hawaii have found some mineralogical surprises in the Moon's largest impact crater.
Data from the Moon Mineralogy Mapper that flew aboard India's Chandrayaan-1 lunar orbiter shows a diverse mineralogy in the subsurface of the giant South Pole Aitken basin.
The differing mineral signatures could be reflective of the minerals dredged up at the time of the giant impact 4 billion years ago, ...
In power electronics systems bonded connections create the central electrical connections between adjoining surfaces.
The quality of these bonded connections is one of the main factors that determines the reliability and availability of drive systems in electric vehicles, and hence constitutes a major design challenge for German auto manufacturers aiming to electrify their vehicles.
Now the partners participating in the RoBE (Robust Bonds in ...
International team of scientists develops new feedback method for optimizing the laser pulse shapes used in the control of chemical reactions
In many ways, traditional chemical synthesis is similar to cooking. To alter the final product, you can change the ingredients or their ratio, change the method of mixing ingredients, or change the temperature or pressure of the environment of the ingredients.
Like an accomplished chef, chemists have become very skilled ...
A genetic defect protects mice from infection with influenza viruses
A new study published in the scientific journal PLOS Pathogens points out that mice lacking a protein called Tmprss2 are no longer affected by certain flu viruses.
The discovery was made by researchers from the Helmholtz Centre for Infection Research (HZI) in Braunschweig in collaboration with colleagues from Göttingen and ...
The Light: Global study gets underway with online user survey
Light has a fundamental impact on our sense of well-being and performance. In cooperation with Zumtobel, a supplier of lighting solutions, Fraunhofer IAO has launched a global user survey of lighting quality in offices. The objective is to identify the best lighting conditions for a variety of spaces and lighting ...
10.12.2013 | Physics and Astronomy
10.12.2013 | Agricultural and Forestry Science
10.12.2013 | Power and Electrical Engineering
10.12.2013 | Event News
05.12.2013 | Event News
04.12.2013 | Event News