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

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 Loriaux, Eduardo Firpo, Jorge E. Cortes, Shannon McWeeney, Thomas O'Hare, James M. Roberts, Brian Druker, Michael W. Deininger

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 (p27CK-) 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 (p27T187A) or nuclear retention (p27S10A) 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.

Original languageEnglish (US)
Pages (from-to)3260-3273
Number of pages14
JournalBlood
Volume124
Issue number22
DOIs
StatePublished - Nov 20 2014

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Oncogene Proteins
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Tumors
Leukemia
Cyclin-Dependent Kinases
Protein-Tyrosine Kinases
Phosphotransferases
Neoplasms
Cells
Apoptosis
Myeloid Cells
Oncogenes
Drug Resistance
Carcinogenesis
Cytoplasm
Pharmaceutical Preparations
Cell Line
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Agarwal, A., Mackenzie, R. J., Besson, A., Jeng, S., Carey, A., LaTocha, D. H., ... Deininger, M. W. (2014). BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein. Blood, 124(22), 3260-3273. https://doi.org/10.1182/blood-2013-04-497040

BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein. / Agarwal, Anupriya; Mackenzie, Ryan J.; Besson, Arnaud; Jeng, Sophia; Carey, Alyssa; LaTocha, Dorian H.; Fleischman, Angela G.; Duquesnes, Nicolas; Eide, Christopher A.; Vasudevan, Kavin B.; Loriaux, Marc; Firpo, Eduardo; Cortes, Jorge E.; McWeeney, Shannon; O'Hare, Thomas; Roberts, James M.; Druker, Brian; Deininger, Michael W.

In: Blood, Vol. 124, No. 22, 20.11.2014, p. 3260-3273.

Research output: Contribution to journalArticle

Agarwal, A, Mackenzie, RJ, Besson, A, Jeng, S, Carey, A, LaTocha, DH, Fleischman, AG, Duquesnes, N, Eide, CA, Vasudevan, KB, Loriaux, M, Firpo, E, Cortes, JE, McWeeney, S, O'Hare, T, Roberts, JM, Druker, B & Deininger, MW 2014, 'BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein', Blood, vol. 124, no. 22, pp. 3260-3273. https://doi.org/10.1182/blood-2013-04-497040
Agarwal A, Mackenzie RJ, Besson A, Jeng S, Carey A, LaTocha DH et al. BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein. Blood. 2014 Nov 20;124(22):3260-3273. https://doi.org/10.1182/blood-2013-04-497040
Agarwal, Anupriya ; Mackenzie, Ryan J. ; Besson, Arnaud ; Jeng, Sophia ; Carey, Alyssa ; LaTocha, Dorian H. ; Fleischman, Angela G. ; Duquesnes, Nicolas ; Eide, Christopher A. ; Vasudevan, Kavin B. ; Loriaux, Marc ; Firpo, Eduardo ; Cortes, Jorge E. ; McWeeney, Shannon ; O'Hare, Thomas ; Roberts, James M. ; Druker, Brian ; Deininger, Michael W. / BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein. In: Blood. 2014 ; Vol. 124, No. 22. pp. 3260-3273.
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AU - Mackenzie, Ryan J.

AU - Besson, Arnaud

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AU - Carey, Alyssa

AU - LaTocha, Dorian H.

AU - Fleischman, Angela G.

AU - Duquesnes, Nicolas

AU - Eide, Christopher A.

AU - Vasudevan, Kavin B.

AU - Loriaux, Marc

AU - Firpo, Eduardo

AU - Cortes, Jorge E.

AU - McWeeney, Shannon

AU - O'Hare, Thomas

AU - Roberts, James M.

AU - Druker, Brian

AU - Deininger, Michael W.

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N2 - 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 (p27CK-) 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 (p27T187A) or nuclear retention (p27S10A) 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.

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