Multiple Myeloma Patient Tumors With High Levels of Cereblon Exon-10 Deletion Splice Variant Upregulate Clinically Targetable Pro-Inflammatory Cytokine Pathways

Kubra Karagoz; Matthew Stokes; María Ortiz-Estévez; Fadi Towfic; Erin Flynt; Sarah Gooding; William Pierceall; Anjan Thakurta

doi:10.3389/fgene.2022.831779

Multiple Myeloma Patient Tumors With High Levels of Cereblon Exon-10 Deletion Splice Variant Upregulate Clinically Targetable Pro-Inflammatory Cytokine Pathways

Front Genet. 2022 Feb 9:13:831779. doi: 10.3389/fgene.2022.831779. eCollection 2022.

Authors

Kubra Karagoz¹, Matthew Stokes¹, María Ortiz-Estévez², Fadi Towfic³, Erin Flynt¹, Sarah Gooding^{4

5

6

7}, William Pierceall¹, Anjan Thakurta^{1

7}

Affiliations

¹ Translational Medicine, Bristol Myers Squibb, Summit, NJ, United States.
² Bristol Myers Squibb Center for Innovation and Translational Research Europe, Sevilla, Spain.
³ Bristol Myers Squibb, San Diego, CA, United States.
⁴ MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
⁵ Department of Haematology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
⁶ NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.
⁷ Oxford Centre for Translational Myeloma Research, University of Oxford, Oxford, United Kingdom.

Abstract

Immunomodulatory drugs (IMiDs), including lenalidomide and pomalidomide, are used in the routine treatment for multiple myeloma (MM) patients. Cereblon (CRBN) is the direct molecular target of IMiDs. While CRBN is not an essential gene for MM cell proliferation, the frequency of CRBN genetic aberrations, including mutation, copy number loss, and exon-10 (which includes a portion of the IMiD-binding domain) splicing, have been reported to incrementally increase in later-line patients. CRBN exon-10 splicing has also been shown to be associated with decreased progression-free survival in both newly diagnosed and relapsed refractory MM patients. Although we did not find significant general splicing defects among patients with CRBN exon-10 splice variant when compared to those expressing the full-length transcript, we identified upregulated TNFA signaling via NFKB, inflammatory response, and IL-10 signaling pathways in patients with exon-10 splice variant across various data sets-all potentially promoting tumor growth via chronic growth signals. We examined master regulators that mediate transcriptional programs in CRBN exon-10 splice variant patients and identified BATF, EZH2, and IKZF1 as the key candidates across the four data sets. Upregulated downstream targets of BATF, EZH2, and IKZF1 are components of TNFA signaling via NFKB, IL2/STAT5 signaling pathways, and IFNG response pathways. Previously, BATF-mediated transcriptional regulation was associated with venetoclax sensitivity in MM. Interestingly, we found that an EZH2 sensitivity gene expression signature also correlated with high BATF or venetoclax sensitivity scores in these tumors. Together, these data provide a rationale for investigating EZH2 inhibitors or venetoclax in combination with the next generation CRBN-targeting agents, such as CELMoDs, for patients overexpressing the CRBN exon-10 splice variant.

Keywords: cereblon (CRBN); drug resistance; exon-10; immunomodulatory drugs; multiple myeloma; tazemetostat; venetoclax.