MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27(KIP1.).
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.
Servicio de Hematología and Unidad de Investigación, Hospital Universitario Dr Negrín, Las Palmas, Spain.
M T
MT
Gómez-Casares
E
E
García-Alegria
C E
CE
López-Jorge
N
N
Ferrándiz
R
R
Blanco
S
S
Alvarez
J P
JP
Vaqué
G
G
Bretones
J M
JM
Caraballo
P
P
Sánchez-Bailón
M D
MD
Delgado
J
J
Martín-Perez
J C
JC
Cigudosa
J
J
León
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D000069439:Dasatinib; D015536:Down-Regulation; D041905:Erythroid Cells / Q000187:drug effects; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D010879:Piperazines / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; C489427:MYC protein, human; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D044786:S-Phase Kinase-Associated Proteins; D013844:Thiazoles; D055544:beta-Globins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000068877:Imatinib Mesylate; D000069439:Dasatinib