Abstract
Multiple Myeloma (MM) is an incurable plasma cell cancer that is caused by several chromosomal translocations and gene deletions. Although deregulation of several signaling pathways including the Nuclear Factor-Kappa B (NF-κB) pathway has been reported in MM, the molecular requirement and the crosstalk between NF-κB and its target genes in MM cell survival has been largely unclear. Here, we report that Yin Yang1 (YY1), a target gene for NF-κB, is hyperexpressed in most MM tumor cells obtained from human patients, exhibits constitutive nuclear localization, and is essential for survival of MM cells. Mechanistically, we report a novel YY1-RelA complex formation, which is essential to transcriptionally repress a proapoptotic gene Bim. In line with this, depletion of YY1 or RelA resulted in elevated levels of Bim and apoptosis. Moreover, both YY1 and RelA are recruited to the Bim promoter and are required to repress the Bim promoter. Importantly, depletion of YY1 or RelA almost completely impaired the colony forming ability of MM progenitor cells suggesting that both RelA and YY1 are essential for the survival and growth of MM progenitor cells. Moreover, depletion of either YY1 or RelA completely inhibited MM tumor growth in xenograft models for human myeloma. Thus, a novel RelA-YY1 transcriptional repression complex is an attractive drug target in MM.
Highlights
Multiple Myeloma (MM) is a monoclonal tumor of the plasma cells (PCs) that develop from the post germinal-center (GC) B cells [1,2]
In order to find whether Yin Yang1 (YY1) is active in MM cells, we analyzed its subcellular localization by preparing cytoplasmic and nuclear extracts from the indicated MMCLs [12,25] and found that YY1 is almost exclusively localized to the nucleus (Fig. 1B)
Since Nuclear Factor-Kappa B (NF-kB) is known to be active in many MMCLs [12,13] and is a known regulator of YY1 expression [14], we analyzed the nuclear levels of RelA and found it to be localized to nucleus in the indicated MMCLs (Fig. 1B)
Summary
Multiple Myeloma (MM) is a monoclonal tumor of the plasma cells (PCs) that develop from the post germinal-center (GC) B cells [1,2]. Similar to the long-lived PCs, MM cells depend on the bone marrow (BM) for survival and growth [1,2]. The molecular requirements for the survival and growth of both intramedullary and extramedullary MM tumors are not completely clear. While MM tumors have been classified into different genetic subgroups based on several genetic abnormalities [1,2,3,4,5,6,7], they are largely classified into three distinct groups of chromosomal translocations involving 1) Cyclin D 2) MAF and 3) MMSET/ FGFR3 genes [2]. Of these, activating mutations in the NF-kB pathway is of particular significance in the pathogenesis of MM because NF-kB provides survival and proliferation signals to the MM tumors and will involve other cell types within the BM microenvironment and contributes to the production of extrinsic survival signals by regulating the production of cytokines such as APRIL and BAFF etc [1]
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