CK1δ and CK1ε Signaling Sustains Mitochondrial Metabolism and Cell Survival in Multiple Myeloma.

Unlabelled: Multiple myeloma remains an incurable malignancy due to acquisition of intrinsic programs that drive therapy resistance. Here we report that casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets in multiple myeloma that are necessary to sustain mitochondrial metabolism. Specifically, the dual CK1δ/CK1ε inhibitor SR-3029 had potent in vivo and ex vivo anti-multiple myeloma activity, including against primary multiple myeloma patient specimens.

Metabolic Changes Are Associated with Melphalan Resistance in Multiple Myeloma.

Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge.

Ligation of dendritic cell-associated lectin-1 induces partial maturation of human monocyte derived dendritic cells.

Dendritic cell-associated lectin-1 (DCAL-1), also known as C-type lectin-like-1 (CLECL1), is a novel C-type lectin-like molecule expressed by antigen presenting cells including dendritic cells (DCs). Here we report that incubation of immature DCs (iDCs) with an anti-DCAL-1 monoclonal antibody (mAb) induced downstream signaling, including phosphorylation of c-Jun N-terminal kinase (JNK) and p44/42 MAP kinase. Furthermore, ligation of DCAL-1 expressed by iDCs specifically enhanced HLA-DR expression, whereas the expression of other co-stimulatory molecules remained unchanged and minimal cytokine secretion was detected.

Nitric oxide and cGMP protein kinase (cGK) regulate dendritic-cell migration toward the lymph-node-directing chemokine CCL19.

Dendritic-cell (DC) migration to secondary lymphoid organs is crucial for the initiation of adaptive immune responses. Although LPS up-regulates CCR7 on DCs, a second signal is required to enable them to migrate toward the chemokine CCL19 (MIP-3beta). We found that the nitric oxide (NO) donor NOR4 provides a signal allowing LPS-stimulated DCs to migrate toward CCL19.

Dendritic-cell-associated C-type lectin 2 (DCAL-2) alters dendritic-cell maturation and cytokine production.

Dendritic-cell (DC)-associated C-type lectin receptors (CLRs) take up antigens to present to T cells and regulate DC functions. DCAL-2 is a CLR with a cytosolic immunoreceptor tyrosine-based inhibitory motif (ITIM), which is restricted to immature DCs (iDCs), monocytes, and CD1a+ DCs. Cross-linking DCAL-2 on iDCs induced protein tyrosine phosphorylation and MAPK activation as well as receptor internalization.

17beta-estradiol (E2) modulates cytokine and chemokine expression in human monocyte-derived dendritic cells.

The effects of estrogen on the immune system are still largely unknown. We have investigated the effect of 17beta-estradiol (E(2)) on human monocyte-derived immature dendritic cells (iDCs). Short-term culture in E(2) had no effect on iDC survival or the expression of cell surface markers.

Cyclic nucleotides promote monocyte differentiation toward a DC-SIGN+ (CD209) intermediate cell and impair differentiation into dendritic cells.

Recruitment of monocytes into tissues and their differentiation into macrophages or dendritic cells (DCs) depend on the microenvironment of the inflammatory site. Although many factors affecting this process have been identified, the intracellular signaling pathways implicated are poorly understood. We found that cyclic nucleotides regulate certain steps of monocyte differentiation into DCs.

Macrophage- and dendritic cell--dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF.

Macrophages and dendritic cells play an important role in regulating B-cell responses, including proliferation to antigens such as trinitrophenyl (TNP)-Ficoll and TNP-Brucella abortus. However, the mechanisms and molecule(s) that regulate these processes are relatively undefined. In this report, we show that human macrophages generated in vitro strongly costimulate proliferation of dense human tonsillar B cells ligated via their B-cell antigen receptor (BCR) but not proliferation via CD40.

Dendritic cell-associated lectin-1: a novel dendritic cell-associated, C-type lectin-like molecule enhances T cell secretion of IL-4.

We have characterized dendritic cell (DC)-associated lectin-1 (DCAL-1), a novel, type II, transmembrane, C-type lectin-like protein. DCAL-1 has restricted expression in hemopoietic cells, in particular, DCs and B cells, but T cells and monocytes do not express it. The DCAL-1 locus is within a cluster of C-type lectin-like loci on human chromosome 12p12-13 just 3' to the CD69 locus.

Characterization of human inducible costimulator ligand expression and function.

The inducible costimulator (ICOS) is the newest member of the CD28/CD152 receptor family involved in regulating T cell activation. We constructed a soluble-Ig fusion protein of the extracellular domain of human ICOS and used it as a probe to characterize expression patterns of the ICOS ligand (ICOSL). ICOSIg did not bind to CD80- or CD86-transfected Chinese hamster ovary cell lines, demonstrating that ICOSL is distinct from those ligands identified for CD28/CD152.

Differential role for p38 mitogen-activated protein kinase in regulating CD40-induced gene expression in dendritic cells and B cells.

We investigated whether human monocyte-derived dendritic cells (DCs) differed from tonsillar B cells in the set of cell fate genes they express constitutively and in the way these genes are affected after CD40 ligation. In particular, Bcl-2, TNF receptor-associated factor-2 (TRAF2), and TRAF4 were clearly inducible via CD40 in B cells but not in DCs. DCs, unlike B cells, were induced to increase expression of IL-1beta, IL-1Ra, IL-8, IL-12 p40, RANTES, macrophage inflammatory protein-1alpha, and monocyte chemoattractant protein-1 after CD40 ligation.

Isolation and characterization of macaque dendritic cells from CD34(+) bone marrow progenitors.

We have developed a method for isolating and characterizing pigtailed macaque dendritic cells (DCs) generated from CD34(+) bone marrow (BM) progenitors based on methods previously developed for isolating human DCs. Macaque DCs displayed a characteristic morphology and were potent stimulators of allogeneic T cell proliferation. They expressed a set of DC-associated markers, such as MHC class II, CD1a, CD4, CD11a, CD40, CD58, CD80, CD83, CD86, and CXCR4.

Characterization of the expression and gene promoter of CD22 in murine B cells.

CD22 is a B cell-restricted surface molecule which may play an important role in interactions between B cells and other cells and in regulating signals through the B cell receptor (BCR) complex. Here we have examined whether the mouse is a suitable in vivo model for studying CD22 functions. In primary and secondary lymphoid organs of adult mice CD22 is on all mature B cells, including resting IgM+IgD+ B cells, IgG+ HSA(lo) memory B cells, syndecan+ plasma cells and CD5+ B cells, but it is not on immature IgM+IgD- B cells.

Functional CD40 ligand expressed by human blood dendritic cells is up-regulated by CD40 ligation.

We examined whether human blood dendritic cells (DCs) express a functional ligand for CD40 (CD40L). Human blood DCs expressed significant amounts of cell surface CD40L identical to that expressed on activated T cells, as detected by mAb to CD40L or a chimeric CD40.Ig fusion protein (CD40.