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Key Points MiR-146a expression is induced by TLR ligation expressed in pDCs. MiR-146a regulates pDC effector functions, including cytokine production and costimulatory capacity.

The spindle assembly checkpoint kinase TTK (Mps1) is a key regulator of chromosome segregation and is the subject of novel targeted therapy approaches by small-molecule inhibitors. Although the first TTK inhibitors have entered phase I dose escalating studies in combination with taxane chemotherapy, a patient stratification strategy is still missing. With the aim to identify a genomic biomarker to predict the response of tumor cells to TTK inhibitor therapy, we profiled a set of preclinical and clinical TTK inhibitors from different chemical series on a panel of 66 genetically characterized cell lines derived from different tumors (Oncolines). Cell lines harboring activating mutations in the gene, encoding the Wnt pathway signaling regulator β-catenin, were on average up to five times more sensitive to TTK inhibitors than cell lines wild-type for The association of -mutant status and increased cancer cell line sensitivity to TTK inhibition was confirmed with isogenic cell line pairs harboring either mutant or wild-type Treatment of a xenograft model of a -mutant cell line with the TTK inhibitor NTRC 0066-0 resulted in complete inhibition of tumor growth. Mutations in occur at relatively high frequency in endometrial cancer and hepatocellular carcinoma, which are known to express high levels. We propose mutant as a prognostic drug response biomarker, enabling the selection of patients most likely to respond to TTK inhibitor therapy in proof-of-concept clinical trials. .

Plasmacytoid dendritic cells (pDCs) selectively express Toll-like receptor (TLR)- IntroductionPlasmacytoid dendritic cells (pDCs) form a unique subset within the DC lineage. In contrast to conventional dendritic cells (cDCs), pDCs express Toll-like receptor (TLR)-7 and TLR-9, which recognize viral and microbial single-stranded RNA or doublestranded DNA, respectively (reviewed in Liu 1 ). TLR activation in pDCs leads to rapid secretion of high amounts of type I interferons (IFNs), which initiate antiviral immune responses. In addition, pDCs mature in response to autocrine production of proinflammatory cytokines such as IL-6 and tumor necrosis factor (TNF)-␣. Collectively, this contributes to activation of T, B, and NK cells (reviewed in Lande and Gilliet 2 ). pDCs originate from hematopoietic progenitor cells (HPCs) in the bone marrow, but can also develop in the thymus. 3 Although both myeloid and lymphoid precursors give rise to pDCs, myeloid derivation is predominant (reviewed by Naik 4 ) and depends on Fms-like kinase 3 ligand (Flt3L). 5 The ETS family member Spi-B is required for pDC development, because both in vitro and in vivo human HPCs failed to give rise to pDCs when inhibiting Spi-B expression. 6 Spi-B shares with other ETS members a conserved ETS domain that mediates DNA binding. 7 Spi-B is a hematopoietic cell-specific transcription factor 8 and is expressed, in addition to pDCs, in CD34 ϩ HPCs, 9 pro-T cells, 10 and mature B cells. 9 Spi-B potently regulates lineage commitment during human hematopoiesis as its overexpression in HPCs blocks T, B, and NK cell development, but promotes pDC development. 6 Despite the importance of Spi-B in development of immune cells, little is known about its direct target genes. In mice, Spi-B may act by indirectly promoting the activity of the E-protein E2-2, which both in human and mouse is critical for pDC development. 11,12 In human B cells, ectopic expression of Spi-B blocked memory B-cell differentiation into antibody secreting cells by direct transcriptional repression of the PRDM1 and XBP1 genes. 13 pDCs are fragile cells that when cultured in vitro rapidly undergo apoptosis, which can be counteracted by stimulation with TLR-7/9 agonists or cytokines, including IL-3, granulocyte macrophage-colony stimulating factor (GM-CSF), or IFN-␣. 14 Apoptosis is a highly regulated process that serves to remove superfluous, damaged, or infected cells and therefore to maintain cellular homeostasis (reviewed by Elmore 15 ). Apoptosis and cell survival are intimately linked, because their regulation is based on the balance between proapoptotic and antiapoptotic (survival) regulators. Members of the Bcl-2 family regulate the intrinsic pathway of apoptosis through control of the outer mitochondrial membrane (OMM) integrity. Proapoptotic members such as Bak, Bax, Bim, and Noxa share a so-called Bcl-2 homology domain, which promote OMM permeability leading to the release of cytochrome C in the cytoplasm and apoptosis induction. Antiapoptotic members, including Bcl-2, Bcl-xL, Bcl...