Modulation of the p19Arf-pü53 tumor suppressor response to overcome persistence in CML

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“Inherent” insensitivity of CML stem/progenitor cells against ABL-specific kinase inhibitors such as imatinib or the more potent second generation inhibitors, which target the causative oncogene of CML, BCR-ABL, causes persistence of chronic myeloid leukemia (CML). In the previous funding period, we have characterized in more detail the site of persisting disease in different bone marrow compartments of CML patients. We found that persisting CML precursors express low BCR-ABL level and that lack of expression of the interferonregulated gene ICSBP (IRF-8) leads to BCR-ABL-independent apoptosis resistance against ABL-specific kinase inhibitors. Importantly, we described that Interferon alpha (IFN) maintenance therapy – previously shown to upregulate IRF8 - was associated with stable molecular remissions even after discontinuation of imatinib.In this funding period we will ask, whether BCR-ABL expression level control elicitation of the p19Arf-p53-mediated tumor suppressive response, and thus enable persistence in CML. Secondly, we will study the hypothesis that IFN amplifies via induction of IRF8 sensing of oncogenic stress signals initiated by BCR-ABL. This could have important therapeutic implications to overcome stem cell persistence in CML.