Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150566/1/bjh15969.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150566/2/bjh15969_am.pd

Mitochondrial Localization and Pro-apoptotic Effects of the Interferon-inducible Protein ISG12a

ISG12a is one of the most highly induced genes following treatment of cells with type I interferons (IFNs). The encoded protein belongs to a family of poorly characterized, low molecular weight IFN-inducible proteins that includes 6–16 (G1P3), 1–8U (IFITM3), and 1–8D (IFITM2). Our studies demonstrate that the ISG12a protein associates with or inserts into the mitochondrial membrane. Transient expression of ISG12a led to decreased viable cell numbers and enhanced sensitivity to DNA-damage induced apoptosis, effects that were blocked by Bcl-2 co-expression or treatment with a pan-caspase inhibitor. ISG12a enhanced etoposide induced cytochrome c release, Bax activation and loss of mitochondrial membrane potential. siRNA-mediated inhibition of ectopic ISG12a protein expression prevented the sensitization to etoposide-induced apoptosis and also decreased the ability of IFN-β pretreatment to sensitize cells to etoposide, thereby demonstrating a role for ISG12a in this process. These data suggest that ISG12a contributes to IFN-dependent perturbation of normal mitochondrial function, thus adding ISG12a to a growing list of IFN-induced proteins that impact cellular apoptosis

Biological and Clinical Properties of the Type 1 Interferons

Interferons (IFNs) are class 2 cytokines that carry out important physiological functions in higher vertebrates, particularly in the regulation of host adaptive and innate immune responses. The complex type 1 IFN family, which includes IFN-α and IFN-β, will be the focus of this chapter. Virus and other innate immune stimuli induce expression of type 1 IFNs, which then act on responsive cells to establish an antiviral state. Type 1 IFN effects are mediated by the protein products of IFN-responsive genes, the identities and functions of which are only now starting to emerge fully. In a clinical setting, type 1 IFNs, IFN-α in particular, have shown effectiveness against a variety of malignancies. Current efforts aimed at improving pharmacokinetic and pharmacodynamic profiles of IFNs, identifying subtypes with novel biological activities and/or establishment of combined treatment modalities involving type 1 IFNs should lead to future improvements in therapeutic effectiveness

Involvement of Noxa in Mediating Cellular ER Stress Responses to Lytic Virus Infection

Noxa is a Bcl-2 homology domain-containing pro-apoptotic mitochondrial protein. Noxa mRNA and protein expression are upregulated by dsRNA or virus, and ectopic Noxa expression enhances cellular sensitivity to virus or dsRNA-induced apoptosis. Here we demonstrate that Noxa null baby mouse kidney (BMK) cells are deficient in normal cytopathic response to lytic viruses, and that reconstitution of the knockout cells with wild-type Noxa restored normal cytopathic responses. Noxa regulation by virus mirrored its regulation by proteasome inhibitors or ER stress inducers and the ER stress response inhibitor salubrinal protected cells against viral cytopathic effects. Noxa mRNA and protein were synergistically upregulated by IFN or dsRNA when combined with ER stress inducers, leading to Noxa/Mcl-1 interaction, activation of Bax and pro-apoptotic caspases, degradation of Mcl-1, loss of mitochondrial membrane potential and initiation of apoptosis. These data highlight the importance of ER stress in augmenting the expression of Noxa following viral infection

Cleavage of NIK by the API2-MALT1 Fusion Oncoprotein Leads to Noncanonical NF-kappa B Activation

Proper regulation of nuclear factor kappa B (NF-kappa B) transcriptional activity is required for normal lymphocyte function, and deregulated NF-kappa B signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-kappa B-inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappa B signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-kappa B pathway in B lymphoproliferative disease.status: publishe