CML: MDC Researchers Uncover Why the Disease Progresses and Becomes Resistant to Drug Treatment

wo 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.

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