TY - JOUR
T1 - Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression
AU - Reavie, Linsey
AU - Buckley, Shannon M.
AU - Loizou, Evangelia
AU - Takeishi, Shoichiro
AU - Aranda-Orgilles, Beatriz
AU - Ndiaye-Lobry, Delphine
AU - Abdel-Wahab, Omar
AU - Ibrahim, Sherif
AU - Nakayama, Keiichi I.
AU - Aifantis, Iannis
N1 - Funding Information:
We would like to thank Dr. B. Sleckman for providing the c-Myc eGFP knockin mice, J. Silva for the anti-p53 shRNA vector, and W. Pear for the Bcr-Abl vectors. We would also like to thank the members of the Aifantis lab for valuable advice and discussions and the NYU Flow Cytometry facility for expert cell sorting. I.A. is supported by the National Institutes of Health (RO1CA133379, RO1CA105129, 1RO1CA173636, RO1CA149655, and RO1GM088847), the Leukemia and Lymphoma Society (TRP program grants), the Chemotherapy Foundation, the William Lawrence Blanche Hughes Foundation, and the V Foundation for Cancer Research. L.R. is supported by an NIH Ruth L. Kirchstein Award. S.M.B. is supported by the NYU Hematology/Oncology NIH training grant (5T32HL007151-33) and the NIH institutional training grant (1T32CA160002-01). B.A-O. is supported by the Alexander von Humboldt Foundation. I.A. is a Howard Hughes Medical Institute Early Career Scientist. We would like to dedicate this paper to our mice lost in the fury of hurricane Sandy.
PY - 2013/3/18
Y1 - 2013/3/18
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84876434253
UR - https://www.scopus.com/pages/publications/84876434253#tab=citedBy
U2 - 10.1016/j.ccr.2013.01.025
DO - 10.1016/j.ccr.2013.01.025
M3 - Article
C2 - 23518350
AN - SCOPUS:84876434253
SN - 1535-6108
VL - 23
SP - 362
EP - 375
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -
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