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

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 CRL4^CRBN E3 ubiquitin ligase complex, leading to the acquisition of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3), casein kinase 1 α (CK1α), and zinc finger protein 91 (ZFP91) as neosubstrates. IMiDs are effective against multiple myeloma because of 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 as a result of 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 4 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 8 PEL cell lines tested, and surprisingly, IMiDs triggered downregulation of IRF4 expression independently of both IKZF1 and IKZF3. Reexpression 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.

SUBMITTER: Patil A

PROVIDER: S-EPMC6085990 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Primary effusion lymphomas (PELs) are specifically associated with KSHV/HHV-8 infection, and most frequently occur in HIV-positive individuals as lymphomatous effusions in the serous cavities without a detectable solid tumor mass. Most PELs have concomitant EBV infection, suggesting that EBV is an important pathogenetic co-factor, although other as yet unidentified cofactors, such as cellular genetic alterations, are also likely to play a role. Lymphomatous effusions that lack KSHV also occur; these are frequently EBV-associated in the setting of HIV infection. Here we used gene expression profile analysis to determine the viral impact on cellular gene expression and the pathogenesis of these lymphomatous effusions. We used the Affymetrix HG-U133A microarray to analyze the gene expression profile of these effusion lymphomas (three virologic groups: KSHV-positive EBV-positive PELs, KSHV-positive EBV-negative PELs and KSHV-negative EBV-positive lymphomatous effusions). Nine cell lines derived from patients with lymphomatous effusions (three from each virologic group and each cell line was done in duplicates.) and three PEL patient samples were used in the study. Our results suggest that KSHV-positive PELs are very different from KSHV-negative lymphomatous effusions, and the genes that are differentially expressed include apoptosis regulators, cell cycle regulators, transcriptional factors and signal transduction regulators. KSHV clearly plays a dominant role in the phenotype of PEL. Within the KSHV-positive PELs, two subgroups can be identified, which were correlated with their EBV viral status. Among these genes (45 gene probes), four were regulators of the MAP kinase pathway that were up-regulated in the KSHV-positive, EBV-negative PELs, suggesting that in the absence of EBV, events that lead to the activation of the MAP kinase pathway may act as a cofactor for the development of PEL. Next we determined whether we could predict the viral status of the three primary patient cases of PEL based on the 45 gene probes that were differentially expressed in KSHV-positive cell lines according to EBV status (pt. 1: KSHV-positive, EBV-positive; Pt. 2: KSHV-positive, low proportion of EBV-positive; pt. 3: KSHV-positive EBV-negative), and we could. Samples: KSHV-positive EBV-positive cell lines: BC-1, BC-2, BC-5 KSHV-positive EBV-negative cell lines: BC-3, BCBL-1, PEL-5 KSHV-negative EBV-positive cell lines: IBL4, SM1, BCKN-1 pt. 1: KSHV-positive, EBV-positive pt. 2: KSHV-positive, EBV-positive (low number of positive cells) pt. 3: KSHV-positive, EBV-negative Keywords: other

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

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