Abstract
NFkB activity is critical for survival and proliferation of normal lymphoid cells and many kinds of B-cell tumors, including multiple myeloma (MM). NFkB activating mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NFkB. Mutations that activate NFkB-inducing kinase (NIK) protein are the most prevalent among the many kinds of NFkB mutations in MM tumors. NIK is the main activating kinase of the alternative NFkB pathway, although over-expression of NIK also can activate the classical pathway. Two NIK inhibitors and an isomeric control were tested with human myeloma cell lines. These specific NIK inhibitors are selectively cytotoxic for cells with NIK-dependent activation of NFkB. Combination therapy targeting NIK and IKKbeta (as a main kinase of the classical NFkB pathway) represents a promising treatment strategy in MM. NIK inhibitors can also be useful tool for assessing the role of NIK and alternative NFkB pathway in different cells.
Highlights
Multiple myeloma (MM) is a mostly incurable, age dependent monoclonal tumor of long-lived bone marrow plasma cells (PC), usually with significant end organ damage[1]
NFkBinducing kinase (NIK) inhibitors are specific for myeloma cell lines (MMCLs) with NIKdependent NFkB activation
NIK-inhibitors significantly increased the number of AnnexinV(+)/PI(-) and AnnexinV(+)/PI(+) cells in a time– dependent manner only for the two MMCL with NIKdependent activation of NFkB (Fig. 4B-D, Fig. S1A-B). These results show that NIK–inhibitors, in a dose- and time-dependent manner, induced apoptosis in MMCLs that have mutations leading to the activation of NIK
Summary
Multiple myeloma (MM) is a mostly incurable, age dependent monoclonal tumor of long-lived bone marrow plasma cells (PC), usually with significant end organ damage[1]. It is the second most common hematopoietic malignancy, with an incidence of about 20,000 per year in the United States[2]. Often MM is preceded by a pre-malignant tumor called monoclonal gammopathy of undetermined significance (MGUS), with a prevalence of about 3% of individuals over the age of 50[3, 4]. NFkB transcription factors play a key role in the survival and/or proliferation of normal PC, and of MGUS and MM tumors[6,7,8]. The NFkB family of transcription factors is composed of 5 subunits - NFKB1
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