Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression

Linsey Reavie, Shannon M Buckley-McKeown, Evangelia Loizou, Shoichiro Takeishi, Beatriz Aranda-Orgilles, Delphine Ndiaye-Lobry, Omar Abdel-Wahab, Sherif Ibrahim, Keiichi I. Nakayama, Iannis Aifantis

Research output: Contribution to journalArticle

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Abstract

The molecular mechanisms regulating leukemia-initiating cell (LIC) function are of important clinical significance. We use chronic myelogenous leukemia (CML) as a model of LIC-dependent malignancy and identify the interaction between the ubiquitin ligase Fbw7 and its substrate c-Myc as a regulator of LIC homeostasis. Deletion of Fbw7 leads to c-Myc overexpression, p53-dependent LIC-specific apoptosis, and the eventual inhibition of tumor progression. A decrease of either c-Myc protein levels or attenuation of the p53 response rescues LIC activity and disease progression. Further experiments showed that Fbw7 expression is required for survival and maintenance of human CML LIC. These studies identify a ubiquitin ligase:substrate pair regulating LIC activity, suggesting that targeting of the Fbw7:c-Myc axis is an attractive therapy target in refractory CML.

Original languageEnglish (US)
Pages (from-to)362-375
Number of pages14
JournalCancer Cell
Volume23
Issue number3
DOIs
StatePublished - Mar 18 2013

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Ubiquitination
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia
Ligases
Ubiquitin
Proto-Oncogene Proteins c-myc
Disease Progression
Neoplasms
Homeostasis
Apoptosis
Survival

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Reavie, L., Buckley-McKeown, S. M., Loizou, E., Takeishi, S., Aranda-Orgilles, B., Ndiaye-Lobry, D., ... Aifantis, I. (2013). Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. Cancer Cell, 23(3), 362-375. https://doi.org/10.1016/j.ccr.2013.01.025

Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. / Reavie, Linsey; Buckley-McKeown, Shannon M; Loizou, Evangelia; Takeishi, Shoichiro; Aranda-Orgilles, Beatriz; Ndiaye-Lobry, Delphine; Abdel-Wahab, Omar; Ibrahim, Sherif; Nakayama, Keiichi I.; Aifantis, Iannis.

In: Cancer Cell, Vol. 23, No. 3, 18.03.2013, p. 362-375.

Research output: Contribution to journalArticle

Reavie, L, Buckley-McKeown, SM, Loizou, E, Takeishi, S, Aranda-Orgilles, B, Ndiaye-Lobry, D, Abdel-Wahab, O, Ibrahim, S, Nakayama, KI & Aifantis, I 2013, 'Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression', Cancer Cell, vol. 23, no. 3, pp. 362-375. https://doi.org/10.1016/j.ccr.2013.01.025
Reavie, Linsey ; Buckley-McKeown, Shannon M ; Loizou, Evangelia ; Takeishi, Shoichiro ; Aranda-Orgilles, Beatriz ; Ndiaye-Lobry, Delphine ; Abdel-Wahab, Omar ; Ibrahim, Sherif ; Nakayama, Keiichi I. ; Aifantis, Iannis. / Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression. In: Cancer Cell. 2013 ; Vol. 23, No. 3. pp. 362-375.
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