Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Chronic Myeloid Leukemia: Why the Disease Progresses and Becomes Resistant to Drug Treatment

08.10.2013
Cancer researchers of the Max Delbrück Center (MDC) Berlin-Buch, have identified a molecular mechanism of chronic myeloid leukemia (CML) that causes the disease to progress and become resistant to drug treatment.

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.

Direct association
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.

Contact:
Barbara Bachtler
Press Department
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
Robert-Rössle-Strasse 10
13125 Berlin, Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de

Barbara Bachtler | Max-Delbrück-Centrum
Further information:
http://www.mdc-berlin.de/

More articles from Health and Medicine:

nachricht NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)

nachricht High speed video recording precisely measures blood cell velocity
15.11.2017 | ITMO University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A “cosmic snake” reveals the structure of remote galaxies

The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.

Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...

Im Focus: Visual intelligence is not the same as IQ

Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.

That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...

Im Focus: Novel Nano-CT device creates high-resolution 3D-X-rays of tiny velvet worm legs

Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.

During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....

Im Focus: Researchers Develop Data Bus for Quantum Computer

The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.

Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...

Im Focus: Wrinkles give heat a jolt in pillared graphene

Rice University researchers test 3-D carbon nanostructures' thermal transport abilities

Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Ecology Across Borders: International conference brings together 1,500 ecologists

15.11.2017 | Event News

Road into laboratory: Users discuss biaxial fatigue-testing for car and truck wheel

15.11.2017 | Event News

#Berlin5GWeek: The right network for Industry 4.0

30.10.2017 | Event News

 
Latest News

Antarctic landscape insights keep ice loss forecasts on the radar

20.11.2017 | Earth Sciences

Filling the gap: High-latitude volcanic eruptions also have global impact

20.11.2017 | Earth Sciences

Water world

20.11.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>