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CK1α and IRF4 are essential and independent effectors of immunomodulatory drugs in primary effusion lymphoma

Ajinkya Patil, Mark Manzano and Eva Gottwein

Key points

  • CK1α is essential for the survival of PEL cell lines and its degradation mediates toxicity of immunomodulatory drugs.

  • Loss of IRF4 expression is a CK1α-, IKZF1-, and IKZF3-independent arm of immunomodulatory drug toxicity in PEL cell lines.

Abstract

Primary effusion lymphoma (PEL) is an aggressive cancer with few treatment options. The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide have recently been shown to kill PEL cell lines and lenalidomide is in clinical trials against PEL. IMiDs bind to the CRL4CRBN E3 ubiquitin ligase complex, leading to the acquisition of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), casein kinase 1 alpha (CK1α) and zinc finger protein 91 (ZFP91) as neosubstrates. IMiDs are effective against multiple myeloma, due to degradation of IKZF1 and IKZF3 and the consequent loss of interferon regulatory factor 4 (IRF4) and MYC expression. Lenalidomide is also effective in chromosome 5q-deletion associated myelodysplastic syndrome, due to degradation of CK1α. An essential IKZF1-IRF4-MYC axis has recently been proposed to underlie the toxicity of IMiDs in PEL. Here, we further investigate IMiD effectors in PEL cell lines, based on genome-wide CRISPR/Cas9 screens for essential human genes. These screens and extensive validation experiments show that, of the four neosubstrates, only CK1α is essential for the survival of PEL cell lines. In contrast, IKZF1 and IKZF3 are dispensable, individually or in combination. IRF4 was critical in all eight PEL cell lines tested and, surprisingly, IMiDs triggered downregulation of IRF4 expression independently of both IKZF1 and IKZF3. Re-expression of CK1α and/or IRF4 partially rescued PEL cell lines from IMiD mediated toxicity. In conclusion, IMiD toxicity in PEL cell lines is independent of IKZF1 and IKZF3 but proceeds through degradation of the neosubstrate CK1α and downregulation of IRF4.

  • Submitted January 19, 2018.
  • Accepted June 27, 2018.