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

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.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Reavie L,Buckley SM,Loizou E,Takeishi S,Aranda-Orgilles B,Ndiaye-Lobry D,Abdel-Wahab O,Ibrahim S,Nakayama KI,Aifantis I

doi

10.1016/j.ccr.2013.01.025

subject

Has Abstract

pub_date

2013-03-18 00:00:00

pages

362-75

issue

3

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(13)00044-5

journal_volume

23

pub_type

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