Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL
kinase inhibitors as
imatinib and
dasatinib. In the CML-derived K562 cell line, low concentrations of
imatinib induce proliferative arrest and erythroid differentiation. We found that
imatinib upregulated the cell cycle inhibitor p27(KIP1) (p27) in a time- and -concentration dependent manner, and that the extent of
imatinib-mediated differentiation was severely decreased in cells with depleted p27. MYC (c-Myc) is a
transcription factor frequently deregulated in human
cancer. MYC is overexpressed in untreated CML and is associated to poor response to
imatinib. Using K562 sublines with conditional MYC expression (induced by Zn(2+) or activated by 4-hydroxy-
tamoxifen) we show that MYC prevented the erythroid differentiation induced by
imatinib and
dasatinib. The differentiation inhibition is not due to increased proliferation of MYC-expressing clones or enhanced apoptosis of differentiated cells. As p27 overexpression is reported to induce erythroid differentiation in K562, we explored the effect of MYC on
imatinib-dependent induction of p27. We show that MYC abrogated the
imatinib-induced upregulation of p27 concomitantly with the differentiation inhibition, suggesting that MYC inhibits differentiation by antagonizing the
imatinib-mediated upregulation of p27. This effect occurs mainly by p27
protein destabilization. This was in part due to MYC-dependent induction of SKP2, a component of the
ubiquitin ligase complex that targets p27 for degradation. 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.