ZFP91 and IKZF1 Cooperatively Promote IMiD Resistance in T-Cell Lymphomas

The immunomodulatory (IMiD) agents, such as lenalidomide, are highly effective treatment for several B cell lymphomas but have poor efficacy in T cell lymphomas (TCLs). Here, we show that IKZF1 is a key drug target and vulnerability in lenalidomide sensitive TCL cells. However, TCLs are largely resistant and become less dependent on IKZF1. Instead, ZPF91 functions as a transcription factor (TF) and coregulates cell survival with IKZF1 in TCL cells that develop resistance to lenalidomide. Aberrant upregulation of CSNK2B, which leads to c-Jun inactivation, contributes to an enhanced TF activity of ZFP91 and suppresses immune activation triggered by lenalidomide. Although ZFP91 can be better targeted by pomalidomide compared to lenalidomide, an inefficient degradation of IKZF1 and ZFP91 widely exists among IMiD-resistance TCLs. A novel CELMoD agent CC-92480, with markedly increased potency and similar substrate selectivity, can overcome IMiD-resistance across multiple TCL subtypes by near complete degradation of IKZF1 and ZFP91. Overall design: We generated three independent pools of lenalidomide-resistant SU-DHL-1 cells by long-term culture in the presence of increasing concentrations of lenalidomide. We then cultured these resistant cells in the absence of lenalidomide for at least 2 months to generate lenalidomide-regrown lines. RNA-seq, ChIP-seq and PRO-seq were performed in SU-DHL-1 parental and len-regrown cells. RNA-seq were also performed in SUDHL1 parental (P) and len-regrown (RG) cells with ZFP91 knockout cells, and in SUDHL1 and KIJK cells with CSNK2B overexpression cells. ZFP91 and Histone marks ChIP-seq were also performed in some other T-cell lymphoma cell lines.