The inducible cyclic adenosine 3’,5’-monophosphate early repressor (ICER) enhances drug sensitivity in acute myeloid leukemia

Abstract

e22045 Background: The Inducible Cyclic Adenosine 3’,5’-monophosphate early repressor (ICER) is a transcription factor that principally counteracts the cAMP response element binding protein (CREB) activity. CREB was previously demonstrated to be overexpressed in acute leukemia, whereas ICER was found rapidly degradated being unable to control gene transcription. ICER exogenous expression was demonstrated to repress CREB targets preventing leukemia progression. We hypothesized that ICER restoration deserves a special consideration for playing a role in CREB oncogenic feature and in modeling leukemic cell phenotype. Methods: We constructed an expression vector for ICER and induced its exogenous expression in HL60 cells (HL60+ICER). We monitored transcription and translation of a series of genes involved in different pathways by quantitative gene expression and western blot analysis. We investigate ICER's role in cell death after treatment with chemotherapic drugs. Results: We revealed that ICER was able to control gene expression in leukemia, principally of genes involved in cell death and survival. In particular, we focused on DUSP1 and DUSP4 phosphatases which were found significantly repressed. HL60+ICER after being treated with drugs increased apoptosis. Cell cycle analyses revealed a block in G2 phase, a lowered cell proliferation and clonogenic potential with respect to HL60 treated at the same conditions. DUSPs downstream targets (IL6, RB, RAS) were lowered expressed and p38 constitutively phosphorylated confirming their role in mediating cellular stress. ICER driven apoptosis was found to be caspases mediated. An enhanced activity of p38 was observed in treated HL60+ICER, and by the use of specific p38 inhibitors apoptosis decreased. Other possible apoptotic pathways (AKT, ERK, JNK) were excluded because found severely disrupted. Conclusions: Finally, we described an enhanced sensibility to drugs in HL60 induced by ICER exogenous expression and that p38 stress signaling pathway is the direct target of this phenomenon. The ability of ICER to modify leukemic cells phenotype respect to chemotherapeutic treatment gave an important information for targets and therapeutic possibilities. No significant financial relationships to disclose.