Regulation of c-Myc Ubiquitination Controls Chronic Myelogenous Leukemia Initiation and Progression
Menée in vitro et in vivo, cette étude met en évidence le rôle essentiel joué par une ubiquitine-ligase, Fbw7, dans la régulation des cellules souches de leucémie myéloïde chronique
The molecular mechanisms regulating leukemia-initiating cell (LIC) function are of important clinical significance. We use chronic myelogenous leukemia (CML) as a model of LIC-dependent malignancy and identify the interaction between the ubiquitin ligase Fbw7 and its substrate c-Myc as a regulator of LIC homeostasis. Deletion of Fbw7 leads to c-Myc overexpression, p53-dependent LIC-specific apoptosis, and the eventual inhibition of tumor progression. A decrease of either c-Myc protein levels or attenuation of the p53 response rescues LIC activity and disease progression. Further experiments showed that Fbw7 expression is required for survival and maintenance of human CML LIC. These studies identify a ubiquitin ligase:substrate pair regulating LIC activity, suggesting that targeting of the Fbw7:c-Myc axis is an attractive therapy target in refractory CML. º Fbw7 function is essential for the initiation and progression of CML º Fbw7 deletion leads to c-Myc overexpression and activation of the p53 pathway º c-Myc is an Fbw7 substrate in CML-initiating cells º FBW7 is required for maintenance of human CML-initiating cells