title: 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.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
authors.forename: Anupriya
authors.identifier: http://orcid.org/0000-0002-8319-6162
authors.initials: A
authors.lastname: Agarwal
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Mackenzie
authors.affiliation: Cancer Research Center of Toulouse, INSERM Unité Mixte de Recherche 1037, Université de Toulouse, Toulouse, France;
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besson
authors.affiliation: Division of Bioinformatics & Computational Biology, Knight Cancer Institute.
authors.forename: Sophia
authors.initials: S
authors.lastname: Jeng
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
authors.forename: Alyssa
authors.initials: A
authors.lastname: Carey
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
authors.forename: Dorian H
authors.initials: DH
authors.lastname: LaTocha
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
authors.forename: Angela G
authors.initials: AG
authors.lastname: Fleischman
authors.affiliation: Cancer Research Center of Toulouse, INSERM Unité Mixte de Recherche 1037, Université de Toulouse, Toulouse, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Duquesnes
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR; Howard Hughes Medical Institute, and.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
authors.forename: Kavin B
authors.initials: KB
authors.lastname: Vasudevan
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR; Department of Pathology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
authors.forename: Marc M
authors.initials: MM
authors.lastname: Loriaux
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Eduardo
authors.initials: E
authors.lastname: Firpo
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Division of Bioinformatics & Computational Biology, Knight Cancer Institute.
authors.forename: Shannon
authors.initials: S
authors.lastname: McWeeney
authors.affiliation: Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: James M
authors.initials: JM
authors.lastname: Roberts
authors.affiliation: Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR; Howard Hughes Medical Institute, and.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015513:Oncogene Proteins / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics
chemical_list: C581634:BCR-ABL1 fusion protein, human; D015513:Oncogene Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016044:Fusion Proteins, bcr-abl