FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-cell Lymphoma Cells.
Rizwan SaffieNan ZhouDelphine RollandÖzlem ÖnderVenkatesha BasrurSydney CampbellKathryn E WellenKojo S J Elenitoba-JohnsonBrian C CapellLuca BusinoPublished in: Cancer research (2020)
Mature B-cell neoplasms are the fifth most common neoplasm. Due to significant heterogeneity at the clinical and genetic levels, current therapies for these cancers fail to provide long-term cures. The clinical success of proteasome inhibition for the treatment of multiple myeloma and B-cell lymphomas has made the ubiquitin pathway an important emerging therapeutic target. In this study, we assessed the role of the E3 ligase FBXW7 in mature B-cell neoplasms. FBXW7 targeted the frequently inactivated tumor suppressor KMT2D for protein degradation, subsequently regulating gene expression signatures related to oxidative phosphorylation (OxPhos). Loss of FBXW7 inhibited diffuse large B-cell lymphoma cell growth and further sensitized cells to OxPhos inhibition. These data elucidate a novel mechanism of regulation of KMT2D levels by the ubiquitin pathway and uncover a role of FBXW7 in regulating oxidative phosphorylation in B-cell malignancies. SIGNIFICANCE: These findings characterize FBXW7 as a prosurvival factor in B-cell lymphoma via degradation of the chromatin modifier KMT2D.
Keyphrases
- diffuse large b cell lymphoma
- gene expression
- epstein barr virus
- induced apoptosis
- cell cycle arrest
- genome wide
- multiple myeloma
- dna methylation
- small molecule
- dna damage
- transcription factor
- single cell
- endoplasmic reticulum stress
- signaling pathway
- drug delivery
- cell proliferation
- copy number
- cancer therapy
- young adults
- low grade
- deep learning
- replacement therapy
- drug induced