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 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
“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
4Institute of Molecular Tumor Biology - IMTB, Medical Faculty of the University of Muenster, Robert-Koch-Str. 43, 48149, Münster, Germany.Contact:
Barbara Bachtler | Max-Delbrück-Centrum
Further reports about: > CML > Cancer treatment > Drug Delivery > MDC > Medicine > Molecular Target > Parkinson’s Disease > blood cell > cancer research > chronic insomnia > drug treatment > leukemia > myeloid > regulatory factor > signaling pathway > stem cells > tumor suppressor > white blood cell
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