Lenalidomide Induces Ubiquitination, Degradation of CSNK1A1 in Myelodysplastic Syndrome

SAN FRANCISCO—Lenalidomide, an immunomodulatory agent used for the treatment of multiple myeloma and myelodysplastic syndrome with deletion chromosome 5q (del[5q]), induces the ubiquitination and degredation of casein kinase 1A1 (CSNK1A1) by the CRBN-CRL4 E3 ubquitin ligase, a study (Abstract 4) presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition has shown.

Using quantitative proteomics in the myeloid cell line KG-1, researchers found that CSNK1A1 had increased ubiquitination and reduced protein abundance after treatment with lenalidomide. Because CSNK1A1 is encoded in the del(5q) region, the target is a potential target for lenalidomide in myelodysplastic syndrome with del(5q).

Results showed that lenalidomide decreased CSNK1A1 levels in various human cell lines without changing the CSNK1A1 mRNA levels. In addition, lenalidomide increased ubiquitination of CSNK1A1 in all cell lines. The CSNK1A1 levels returned to normal following treatment with MG132, a proteasome inhibitor, and MLN4924, which inhibited Cullin-RING ubiquitin ligase.

In the presence of lenalidomide, CSNK1A1 co-immunoprecipitated with CRBN, suggesting a direct interaction between CSNK1A1 and the substrate adaptor for the ubiquitin ligase.

The researchers next investigated how CSNK1A1 degradation resulted in the specificity of lenalidomide for del(5q) cells. ShRNA-mediated knockdown of CSNK1A1 was found to sensitize CD34⁺ cells to lenalidomide, demonstrating that CSNK1A1 haploinsufficiency may increase the sensitivity of del(5q) cells to lenalidomide.

The authors conclude that del(5q) cells have only one copy of CSNK1A1, thereby making them selectively depleted over wild-type cells, indicating the mechanism behind lenalidomide’s efficacy in del(5q) myelodysplastic syndrome.

“Lenalidomide induces the ubiquination of CSNK1A1 by the CRBN-CRL4 and its subsequent degredation,” Emma C. Fink of Brigham and Women’s Hospital in Boston, MA, said while presenting at the meeting. “We also found that haploinsufficiency of CSNK1A1, sensitizes del(5q) cells to lenalidomide treatment and results in p53-dependent killing.”

Fink also connected their findings to the well-known drug, thalidomide. “We also identified a single, non-conserved amino acid in mouse and human CRBN that determines lenalidomide susceptibility. This amino acid might have contributed to the approval of thalimode and the resulting human tragedies,” she said.

Reference

1. Fink, Emma C., et al. “4 Lenalidomide Induces Ubiquitination and Degradation of CSNK1A1 in MDS with Del(5q).” ASH 2014. Oral Presentation. December 7, 2014.