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. 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.

Regulation of GATA-binding Protein 2 Levels via Ubiquitin-dependent Degradation by Fbw7

“…Therefore, accumulation of GATA2 in Fbw7 ⌬/⌬ mice might inhibit cell cycle entry and cell proliferation of HSCs, and thereby c-Kit hi HSC might be preferentially decreased. In addition, the depletion of Fbw7 promotes c-Myc accumulation and eliminates leukemia-initiating cells via apoptosis (45,54). The Fbw7-mediated control of GATA2 and other Fbw7 substrates, including c-Myc, might participate in self-renewal and maintenance of hematopoietic/ leukemic stem cells.…”

Genetic control of quiescence in hematopoietic stem cells

“…Interestingly, two groups recently showed that Fbw7 and its target, c-Myc, also control the initiation and progression of chronic myeloid leukemia by activating the p53-dependent apoptosis of leukemia-initiating cells. 31,32 There is emerging evidence that metabolic fitness influences the proliferative capacity of stem cells by controlling energy availability. Loss of the tumor suppressor Lkb1 increased the proliferation of HSCs, exhaustion of the stem cell pool, pancytopenia, and impaired the repopulating capacity of HSCs.…”

Mammalian MYC Proteins and Cancer

“…Finally, at the other end of the spectrum, the Ub-mediated proteolysis of MYC has gained considerable attention as an attractive target in cancer, spurred by the fact that the Ub-proteasome system relies on enzymatic (i.e., druggable) activities and is already established as a bona fide way to kill cancer cells [307]. Developing molecules that either accelerate the rate of MYC destruction (e.g., by inhibiting deubiquitylating enzymes that stabilize MYC [113,114]) or massively stabilize MYC to kill cancer stem cells [308] may ultimately prove effective in tumor settings, although these concepts have yet to be reduced to practice.…”