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FBXW7 Triggers Degradation of KMT2D to Favor Growth of Diffuse Large B-cell Lymphoma Cells.

Cancer research (2020-05-01)
Rizwan Saffie, Nan Zhou, Delphine Rolland, Özlem Önder, Venkatesha Basrur, Sydney Campbell, Kathryn E Wellen, Kojo S J Elenitoba-Johnson, Brian C Capell, Luca Busino

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.

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Product Description

ANTI-FLAG® M2 Affinity Gel, purified immunoglobulin, buffered aqueous glycerol solution
Doxycycline hyclate
Cycloheximide, from microbial, ≥94% (TLC)
ANTI-FLAG® antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Hygromycin B, Streptomyces sp., Sterile-Filtered Solution in PBS, Cell Culture-Tested - CAS 31282-04-9 - Calbiochem, Hygromycin B is an aminoglycoside antibiotic that inhibits the growth of prokaryotic and eukaryotic microorganisms and mammalian cells. Inhibits protein synthesis by interfering with the translocation of the 70S ribosome and causes misreading of mRNA.
NAE Inhibitor, MLN4924 - CAS 951950-33-7 - Calbiochem, NAE Inhibitor, MLN4924, CAS 951950-33-7, is an AMP mimetic that forms a NAE-catalyzed NEDD8 adduct, which acts as a tight-binding, ATP-competitive NAE inhibitor (IC50 = 4.7 nM).
Pyrvinium pamoate salt hydrate, ≥98% (HPLC)

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