BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein.

Abstract

Recent studies have revealed that p27, a nuclear cyclin-dependent kinase (Cdk) inhibitor and tumor suppressor, can acquire oncogenic activities upon mislocalization to the cytoplasm. To understand how these antagonistic activities influence oncogenesis, we dissected the nuclear and cytoplasmic functions of p27 in chronic myeloid leukemia (CML), a well-characterized malignancy caused by the BCR-ABL1 tyrosine kinase. p27 is predominantly cytoplasmic in CML and nuclear in normal cells. BCR-ABL1 regulates nuclear and cytoplasmic p27 abundance by kinase-dependent and -independent mechanisms, respectively. p27 knockdown in CML cell lines with predominantly cytoplasmic p27 induces apoptosis, consistent with a leukemogenic role of cytoplasmic p27. Accordingly, a p27 mutant (p27(CK-)) devoid of Cdk inhibitory nuclear functions enhances leukemogenesis in a murine CML model compared with complete absence of p27. In contrast, p27 mutations that enhance its stability (p27(T187A)) or nuclear retention (p27(S10A)) attenuate leukemogenesis over wild-type p27, validating the tumor-suppressor function of nuclear p27 in CML. We conclude that BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. These findings suggest that cytoplasmic mislocalization of p27 despite BCR-ABL1 inhibition by tyrosine kinase inhibitors may contribute to drug resistance, and effective therapeutic strategies to stabilize nuclear p27 must also prevent cytoplasmic mislocalization.

• Authors: Anupriya Agarwal, Ryan J Mackenzie, Arnaud Besson, Sophia Jeng, Alyssa Carey, Dorian H LaTocha, Angela G Fleischman, Nicolas Duquesnes, Christopher A Eide, Kavin B Vasudevan, Marc M Loriaux, Eduardo Firpo, Jorge E Cortes, Shannon McWeeney, Thomas O'Hare, James M Roberts, Brian J Druker, Michael W Deininger
• Journal: Blood (Blood) Vol. 124 Issue 22 Pg. 3260-73 (Nov 20 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 25293778 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society of Hematology.

Chemical References

• BCR-ABL1 fusion protein, human
• Oncogene Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• Fusion Proteins, bcr-abl

Topics

• Animals
• Cell Transformation, Neoplastic (genetics)
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Cytoplasm (metabolism)
• Fusion Proteins, bcr-abl (physiology)
• Genes, Tumor Suppressor
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Oncogene Proteins (metabolism)
• Protein Transport (genetics)