Cyclin D1 Promotes Survival And Chemoresistance By Maintaining Atr And Chek1 Signaling In Tp53-Deficient Mantle Cell Lymphoma Cell Lines

Mantle cell lymphoma (MCL) is a heterogeneous disease, ranging from indolent to aggressive conditions. Prognostic markers that predict aggressive MCL include blastoid cytologic features, high proliferation index (Argatoff et al. 1997), INK4A/ARF locus deletion (Dreyling et al. 1997), TP53 deletion and/or mutations (Greiner et al. 1996), elevated cyclin D1 (CCND1) expression (Rosenwald et al. 2003), and NOTCH1/2 mutations (Kridel et al. 2012, Bea et al. 2013). Among these, TP53 lesions are the most recurrent, suggesting their important role in MCL pathogenesis. In response to DNA damage, TP53 in normal cells activates cell cycle checkpoints to stall DNA replication allowing time for DNA repair or induces apoptosis when damage is severe (Zhou and Elledge. 2000). Tumor cells lacking TP53 function rely on the ATR-CHEK1 signaling for cell cycle checkpoints following DNA damage (Powell et al. 1995). Although both TP53 deficiencies and elevated CCND1 expression levels have been associated with poor survival, possible cooperation of TP53 status and CCND1 expression in aggressive MCL has not been examined.