The ubiquitin-activating enzyme E1 as a therapeutic target for the treatment of leukemia and multiple myeloma

Abstract

The proteasomal pathway of protein degradation involves 2 discrete steps: ubiquitination and degradation. Here, we evaluated the effects of inhibiting the ubiquitination pathway at the level of the ubiquitin-activating enzyme UBA1 (E1).

The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma

“…17 For a detailed description of cell culture, see the supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article).…”

“…Cell viability was also assessed by the Trypan blue exclusion assay and by annexin V and propidium iodide (PI) staining (Biovision), as previously described. 17 Clonogeneic growth assays with fresh primary acute myeloid leukemia (AML) patient and normal hematopoietic stem cells were performed as previously described. 17 For a detailed description of the clonogenic growth assays, see the supplemental Methods.…”

Deubiquitinase Inhibition by Small-Molecule WP1130 Triggers Aggresome Formation and Tumor Cell Apoptosis

“…Small molecules that affect protein ubiquitination and induce tumor cell apoptosis through inhibition of the ubiquitin conjugation or deconjugation enzymes have been described. Novel compounds that affect E1-activating enzyme activity (1)(2)(3) or E3 ligase substrate recognition such as HDM2 and TRAF6 (4, 5) have been described, and preclinical antitumor activity has been reported. Other compounds that affect protein ubiquitination indirectly have also been described, some with important clinical effect.…”

High BRE expression predicts favorable outcome in adult acute myeloid leukemia, in particular among MLL-AF9–positive patients

“…Several of these therapies are currently tested in clinical trials for hematologic malignancies. [9][10][11][12] Recurrent mutations in AML have an impact on disease outcome. Treatment decisions are therefore dependent on the presence or absence of these mutations.…”