LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Abstract

Key Points• LXR activation inhibits BPDCN cell survival through the increase of cholesterol efflux, the inhibition of NF-kB, and IL-3 signaling.• Treatment with LXR agonists can be proposed as a new therapeutic approach for BPDCN.Blastic plasmacytoid dendritic cell (PDC) neoplasm (BPDCN) is an aggressive hematological malignancy with a poor prognosis that derives from PDCs. No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared with those of acute myeloid leukemia and T-acute lymphoblastic leukemia, as well as the transcriptomic signature of primary PDCs. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with 3 signaling pathways associated with leukemic cell survival, namely: NF-kB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor interleukin-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach. (Blood. 2016;128(23):2694-2707

Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

“…The activation of the LXR pathway in PDC reduces the pro-inflammatory cytokine secretion (IL-6 and TNF-α) induced by TLR7 triggering 6 . Moreover, these data obtained in human PDC from healthy donors 6 and in leukemic PDC 99 demonstrate that the LXR pathway interferes with TLR7-induced NF-κB activation at different levels, including a transcriptional repression of p65 NF-κB subunit and a reduced phosphorylation of this NF-κB subunit ( Figure 3) 6, 99 . Pretreatment of leukemic PDC with synthetic LXR agonists also reduces Akt and STAT5 phosphorylation in response to IL-3 ( Figure 3) 99 .…”

“…Moreover, these data obtained in human PDC from healthy donors 6 and in leukemic PDC 99 demonstrate that the LXR pathway interferes with TLR7-induced NF-κB activation at different levels, including a transcriptional repression of p65 NF-κB subunit and a reduced phosphorylation of this NF-κB subunit ( Figure 3) 6, 99 . Pretreatment of leukemic PDC with synthetic LXR agonists also reduces Akt and STAT5 phosphorylation in response to IL-3 ( Figure 3) 99 . LXR stimulation in the PDC cell line CAL-1 increases cholesterol efflux via the upregulation of cholesterol transporters, such as ABCA1 ( Figure 3) 99 .…”

“…Pretreatment of leukemic PDC with synthetic LXR agonists also reduces Akt and STAT5 phosphorylation in response to IL-3 ( Figure 3) 99 . LXR stimulation in the PDC cell line CAL-1 increases cholesterol efflux via the upregulation of cholesterol transporters, such as ABCA1 ( Figure 3) 99 . Although the cholesterol efflux was only tested using this CAL-1 PDC cell line 99 , upregulation of cholesterol transporters at mRNA and protein levels was also observed in human blood-derived PDC treated with LXR agonists 6 .…”

“…LXR stimulation in the PDC cell line CAL-1 increases cholesterol efflux via the upregulation of cholesterol transporters, such as ABCA1 ( Figure 3) 99 . Although the cholesterol efflux was only tested using this CAL-1 PDC cell line 99 , upregulation of cholesterol transporters at mRNA and protein levels was also observed in human blood-derived PDC treated with LXR agonists 6 . Stimulation of cholesterol efflux by the addition of a cholesterol acceptor, APOA1, amplifies the effects of LXR activation in leukemic PDC, including inhibition of the IL-3 signaling pathway (Akt and STAT5 phosphorylation) and cell survival ( Figure 3) 99 .…”

“…Although the cholesterol efflux was only tested using this CAL-1 PDC cell line 99 , upregulation of cholesterol transporters at mRNA and protein levels was also observed in human blood-derived PDC treated with LXR agonists 6 . Stimulation of cholesterol efflux by the addition of a cholesterol acceptor, APOA1, amplifies the effects of LXR activation in leukemic PDC, including inhibition of the IL-3 signaling pathway (Akt and STAT5 phosphorylation) and cell survival ( Figure 3) 99 . This confirms the previous data using statins 97 , and suggests that modifying cholesterol homeostasis in PDC can be useful to limit their detrimental role in pathological situations.…”