MYC antagonizes imatinib-induced differentiation in chronic myeloid leukemia cells through downregulation of p27KIP1

Short Communication.-- et al.Imatinib is a BCR-ABL kinase inhibitor and the most used drug in chronic myeloid leukemia (CML). MYC (c-Myc) is a transcription factor frequently deregulated in human cancer that exerts multiple biological activities, including differentiation inhibition. We found that MYC expression is higher in bone marrow cells form CML patients at diagnosis, as compared with healthy controls. Moreover, high MYC levels at diagnosis correlated with a poorer response to imatinib treatment. One of the major characteristics of CML progression is the loss of cell differentiation. We showed that low concentrations of imatinib induce erythroid differentiation in the CML-derived K562 cell line. We have studied the effect of MYC on the differentiation induced by imatinib using K562 sublines carrying inducible (by zinc cation) or activable (by 4-hydoxy-tamoxifen) MYC alleles. In both cell lines, MYC largely prevented the erythroid differentiation induced by imatinib. The differentiation inhibition mediated by MYC is not due to increased proliferation of MYC-expressing cells or enhanced apoptosis of differentiated cells in the presence of MYC. We previously reported that p27/Kip1 (p27) overexpression induces erythroid differentiation in K562. Thus, we explored the effect of imatinib on p27 levels and we found that imatinib up-regulated p27 in a time- and concentration-dependent manner. siRNA-mediated silencing of p27 antagonized the erythroid differentiation induced by imatinib, indicating that p27 up-regulation is at least in part responsible for differentiation. MYC abrogated the imatinib-induced upregulation of p27KIP1 concomitantly with the differentiation inhibition, suggesting that MYC inhibits imatinib-mediated differentiation of K562 cells by antagonizing p27 up-regulation. We previously reported that MYC induced SKP2, a component of the ubiquitin ligase complex that targets p27 for degradation. MYC was able to induce SKP2 in the presence of imatinib. Thus, MYC-mediated inhibition of the differentiating effect of imatinib in CML cells is in part a consequence of the SKP2 induction of MYC, which in turn would downregulate p27. The results suggest that, although MYC deregulation does not directly confer resistance to imatinib, it might be a factor that contributes to progression of CML through the inhibition of differentiation.Funding for this work was provided by grants SAF11-23796 and ISCIII-RETIC RD06/0020/0017 to JL, FIS 11/00397 to MDD, SAF09-09254 and Fundación Mutua Madrileña to JMP, FIS08-0878 to SA and FIS08-0440 to JCC.Peer Reviewe