Expression data from 12 BPDCN samples, 35 T-ALL samples, and 65 AML samples

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological. We used transcriptomic analysis to investigate LXR pathway, and cholesterol metabolism in leukemic cells. Malignancy with a poor prognosis that derives from plasmacytoid dendritic cells (PDC). 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 to those of acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL), as well as the transcriptomic signature of primary PDC. 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 ATP 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 three signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor IL-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 an 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. Leukemic samples were obtained from patients at diagnosis, with acute leukemia through bone marrow aspirates or blood collection, for RNA extraction and hybridization on Affymetrix microarrays. Acute leukemia were classified according to the standard morphological and immunophenotypic and/or immunohistochemical World Health Organization (WHO) criteria. AML samples were sub-categorised following French-American-British (FAB) classification. T-ALL were sub-categorised as described (Asnafi et al., Blood 2003). The 12 BPDCN were obtained from our national network (authorization number DC-2008-713). Diagnosis was established BPDCN based on histopathology and immunostaining of cutaneous lesions, as described previously (Garnach-Ottou et al., Br J Haematol., 2009; Angelot-Delettre et al., Cytometry A., 2012; Riaz et al., Cancer Control., 2014).