Details

Autor(en) / Beteiligte

• Amari, Keigo
• Sasagawa, Satoru
• Imayoshi, Natsuki
• Toda, Yuki
• Hosogi, Shigekuni
• Imamura, Toshihiko
• Ashihara, Eishi

Titel

The CDK4/6-UCHL5-BRD4 axis confers resistance to BET inhibitors in MLL-rearranged leukemia cells by suppressing BRD4 protein degradation

Ist Teil von

• Biochemical and biophysical research communications, 2022-01, Vol.588, p.147-153

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• Among acute leukemias, mixed-lineage leukemia-rearranged (MLL-r) leukemia is associated with poor prognosis. Bromodomain and extra-terminal inhibitors (BETi) are promising agents for treatment of hematological malignancies; however, the mechanisms underlying sensitivity to BETi and biomarkers to predict sensitivity are yet to be clarified. Here, we established OTX015-resistant MLL-r cell lines (OTX015-R cells) and used them to explore therapeutic targets in BETi-resistant MLL-r leukemia. OTX015-R cells exhibited resistance to various BETi, and levels of bromodomain-containing protein 4 (BRD4) and BRD4-regulated molecules, such as c-MYC and B-cell/CLL lymphoma-2 (BCL-2), were remarkably increased in OTX015-R cells relative to those in the parental cells; however, BRD4 mRNA transcript levels were not elevated. These results suggest that overexpression of BRD4 protein, through suppression of BRD4 degradation, may contribute to BETi-resistance. Notably, expression of ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5) was increased in OTX015-R cells. Further, a UCHL5 inhibitor, b-AP15, and UCHL5 knockdown had antitumor effects by degrading BRD4. In addition, sensitivity to OTX015 was partially recovered in OTX015-R cells pretreated with b-AP15. Furthermore, cyclin-dependent kinase 4/6 (CDK4/6) inhibition decreased UCHL5 expression, suppressed OTX015-R cell proliferation, and induced apoptosis. These results indicate that the CDK4/6-UCHL5-BRD4 axis confers resistance to BETi by suppressing BRD4 degradation. We propose that this pathway is a potential novel therapeutic target in BETi-resistant MLL-r leukemia with BRD4 overexpression. •OTX015-resistant MLL-r leukemia cell lines were established.•BRD4 and UCHL5 expression levels were increased in resistant cells.•UCHL5 inhibition exhibits antitumor effects via degradation of BRD4.•A UCHL5 inhibitor recovers BETi sensitivity in OTX015-resistant cells.•A CDK4/6 inhibitor reduces UCHL5 levels and induces apoptosis in resistant cells.